Anticancer compounds

ABSTRACT

The present invention discloses compounds for inhibition of uncontrolled cell proliferation particularly in cancer stem cells. Particularly, the invention relates to compounds of Formula III to XIV for the treatment of cancer, such as breast and prostate cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of co-pending U.S. patent applicationSer. No. 16/336,460 filed on Mar. 25, 2019, which is hereby incorporatedherein by reference in its entirety. The application Ser. No. 16/336,460is a U.S. National Phase application, under 35 U.S.C. § 371, ofInternational Application no. PCT/IN2018/050237, with an internationalfiling date of Apr. 19, 2018 and claims benefit of India Application no.201621035967 filed on Apr. 20, 2017, and India Application no.201721045003 filed on Dec. 14, 2017; and each of which is herebyincorporated by reference for all purposes.

FIELD OF THE INVENTION

The present invention relates to compounds for inhibition ofuncontrolled cell proliferation, particularly cancer stem cells. Thepresent invention also relates to the compounds for use in the treatmentof cancer.

BACKGROUND OF THE INVENTION

Cancer is a condition in which abnormal cells proliferate and spread atany place in the body. In other words, cancer is an uncontrolled growthof abnormal cells. Cancer is a leading cause of death worldwide. Itremains the second most dreadful disease in India, killing more thanthree million patients each year. It is of major concern in India and isreported to be one of the ten leading causes of deaths in India.

While molecularly-targeted therapies are available for treatment ofcancer for a high price, majority of the world population rely onstandard chemotherapy. The standard anticancer regiment targets most ofthe dividing cancer cells and not quiescent or slow-dividing cancer stemcells (CSCs). Even though, CSCs have been identified a while ago,scientists around the globe are still looking to find CSC-targetedagents and unfortunately, until today, there is none available in themarket to specifically target CSCs.

CSCs and work either alone or in combination with the standard therapiesto provide effective treatment option for the cancer patients.

SUMMARY OF INVENTION

The present invention provides compounds for the treatment of cancer,particularly—cancer stem cells that show preferential toxicity towardsmalignant cells, particularly in cancer cell lines such as breastcancer, and/or prostate cancer cell lines.

In one aspect of the present invention, compound of Formula III isprovided:

where E and Z is selected from C, O, N, S, salts of N such as N, HCl; Qis O, S, —CH₂O—, —NY′, wherein Y′ is selected from —H, alkyl, SOOCH3; R⁵is —H, —Cl, when E and/or Z is —C; R⁶ and R⁷ each independently isselected from —H, alkoxy, alkyl, substituted or unsubstituted aromaticgroup, —NH₂, —NO₂, NHCOCH₃, —CN, —O—, halogen, —OCF₃ or R⁶ and R⁷together form a heterocyclic ring; R⁸ is —H, −Cl, when E and/or Z is —C;R₉ is —CH2-O—CH2, —COOH, —X where X can be F, Cl, Br, alkyl such as—CH₃, —OH, alkoxy such as —OMe, NHCOCH₃, H, NH₂; R¹¹ and R¹² eachindependently is selected from —H, or R¹¹ and R¹² can be substituted orunsubstituted 5- or 6-membered ring, such as lactone, —C(O)O-alkyl suchas —C(O)OC₂H₅; R is selected from

—H, —C(O)CH₂Cl, —SOO—CH₃, —SOOPh, —CH₂C(O)N(CH₃)₂, —C(O)NHPh,—C(O)NHPhOH, —C(S)NHPh, —CH₂Ph, —COAr, —SOOAr, —CONHAr, —CH₂Ar, —CSNHAr,wherein, R¹³ is selected from —OH, —NH₂, —NHCOCH₃, X═F, Cl, Br, alkyl,acetyl, C₃-C₈ acyl group; R¹⁴ is selected from alkoxy, —OMe, —OH, NH₂,—NHCOCH₃, X═F, Cl, Br, alkyl, acetyl, C₃-C₈ acyl group; R¹⁵ is selectedfrom alkoxy, —OMe, —OH, —H, Br, NH₂, X═F, Cl, Br, alkyl, acetyl, C₃-C₈acyl group; R¹⁶ is selected from —H, —CH₂OH, —OH, alkyl, alkoxy; R¹⁷ isselected from alkyl.

In another aspect of the present invention, compound of Formula IV isprovided:

where R⁶ and R⁷ each independently is selected from —H, alkoxy, alkyl,substituted or unsubstituted aromatic group, —NH₂, —NO₂, —NHCOCH₃, —CN,—O—, halogen, —OCF₃ or R⁶ and R⁷ together form a heterocyclic ring; R isselected from:

—H, —C(O)CH₂Cl, SOO—CH₃, —SOOPh, —CH₂C(O)N(CH₃)₂, —C(O)NHPh,—C(O)NHPhOH, —C(S)NHPh, —CH₂Ph, —COAr, —SOOAr, —CONHAr, —CH₂Ar, —CSNHAr;R¹¹ and R¹² each independently is selected from —H, or R¹¹ and R¹² canbe substituted or unsubstituted 5- or 6-membered ring such as lactone,—C(O)O-alkyl such as —C(O)OC₂H₅;

In a preferred aspect of the invention, compound of Formula V isprovided:

In another preferred aspect, compound of Formula VI is provided:

In another aspect, compound of Formula VII is provided:

In another aspect, compound of Formula VIII is provided:

In a further aspect, compound of Formula IX is provided:

In a further aspect, a compound of Formula X is provided:

In a further aspect, a compound of Formula XI is provided:

In a further aspect, a compound of Formula XII is provided:

In a further aspect, a compound of Formula XIII is provided:

In a further aspect, a compound of Formula XIV is provided:

The present invention provides compounds V to XIV for use in treatmentof cancer.

In further aspect of the present invention, compounds of Formula V toXIV for use in the treatment of cancer is provided. The cancer can bebreast, oral, prostate, brain, blood, bone marrow, liver, pancreas,skin, kidney, colon, ovary, lung, testicle, penis, thyroid, parathyroid,pituitary, thymus, retina, uvea, conjunctiva, spleen, head, neck,trachea, gall bladder, rectum, salivary gland, adrenal gland, throat,esophagus, lymph nodes, sweat glands, sebaceous glands, muscle, heart,or stomach cancer.

In a preferred aspect of the present invention, the compounds of FormulaV or VI can be for use in the treatment of breast and/or prostatecancer.

In yet another aspect of the present invention, a pharmaceuticalcomposition having a compound of Formula V to Formula XIV andpharmaceutically acceptable excipient including carrier, adjuvant,vehicle or mixtures thereof is provided. The composition of the presentinvention can be used in the treatment of cancer. The cancer includesbreast, oral, prostate, brain, blood, bone marrow, liver, pancreas,skin, kidney, colon, ovary, lung, testicle, penis, thyroid, parathyroid,pituitary, thymus, retina, uvea, conjunctiva, spleen, head, neck,trachea, gall bladder, rectum, salivary gland, adrenal gland, throat,esophagus, lymph nodes, sweat glands, sebaceous glands, muscle, heart,or stomach cancer.

In a preferred aspect, the composition can be used for the treatment ofbreast and/or prostate cancer.

In a further aspect of the present invention, a method of treatingcancer by administering an effective amount of at least one of compoundsof present invention is provided. In a preferred aspect, a method oftreating cancer including administering an effective amount of compoundof formula V or VI is provided. The method of treatment includingadministering an effective amount of compound of formula V or VI, can befor treating breast cancer and/or a prostate cancer.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 . Shows effect of compound of Formula V on cancer cell linesMDAMB231 and PC3 compared to standard chemo therapeutic drug Cisplatinin MTT assay.

FIG. 2 . Shows effect of compound of Formula V on cancer cell linesMDAMB231 and PC3 compared to standard chemo therapeutic drug Cisplatinin soft Agar Assay.

FIG. 3 Shows the percentage viability of spheres of MDAMB231 in thepresence of compound of Formula V compared to standard chemo therapeuticdrug

FIG. 4 Shows that there is decrease in percentage viability of spheresof PC3 in presence of Formula V compared to standard chemotherapeuticdrug Cisplatin.

FIG. 5 Shows the effect of compound of Formula VI on MDAMB231 and PC3cancer cell lines compared to standard chemo therapeutic drug Cisplatinin MTT assay.

FIG. 6 Shows the effect of compound of Formula VI on MDAMB231 and PC3cancer cell lines compared to standard chemo therapeutic drug Cisplatinin Soft Agar Assay.

FIG. 7 Shows that there is decrease in percentage viability of spheresof MDAMB231 in presence of compound of Formula VI compared to standardchemo therapeutic drug Cisplatin

FIG. 8 shows that there is decrease in percentage viability of spheresof PC3 in presence of compound of Formula VI compared to standardchemotherapeutic drug Cisplatin.

FIG. 9 . Shows compound of Formula VII exhibits higher anticanceractivity on MCF7, MDAMB231, PC3 and DU145 cell lines compared tostandard chemo therapeutic drug Cisplatin in MTT assay.

FIG. 10 . Shows that compound of Formula VII exhibits higher anticanceractivity on MDAMB231. PC3 cell lines compared to standardchemotherapeutic drug Cisplatin in Soft Agar Assay.

FIG. 11 Shows there is decrease in percentage viability of spheres ofMDAMB231 in presence of compound of Formula VII compared to standardchemo therapeutic drug Cisplatin.

FIG. 12 Shows that there is decrease in percentage viability of spheresof PC3 in presence of compound of Formula VII compared to standardchemotherapeutic drug Cisplatin.

FIG. 13 Shows that compound of Formula VIII exhibits higher anticanceractivity on MCF7, MDAMB231, PC3 and DU145 cell lines compared tostandard chemotherapeutic drug Cisplatin in MTT assay.

FIG. 14 Shows that compound of Formula VIII exhibits higher anticanceractivity on MDAMB231, PC3 cell lines compared to standardchemotherapeutic drug Cisplatin in Soft Agar Assay.

FIG. 15 shows that there is decrease in percentage viability of spheresof MDAMB231 in presence of compound of Formula VIII compared to standardchemo therapeutic drug Cisplatin.

FIG. 16 shows that there is decrease in percentage viability of spheresof PC3 in presence of compound of Formula VIII compared to standardchemotherapeutic drug Cisplatin.

FIG. 17 Shows that compound of Formula IX exhibits higher anticanceractivity on MCF7, MDAMB231, PC3, DC145 cell lines compared to standardchemotherapeutic drug Cisplatin in MTT assay.

FIG. 18 Shows compound of Formula IX exhibits higher anticancer activityon MDAMB231, PC3 cell lines compared to standard therapeutic drugCisplatin in Soft Agar Assay.

FIG. 19 Shows that there is decrease in percentage viability of spheresof MDAMB231 in presence of compound of Formula IX compared to standardchemo therapeutic drug Cisplatin.

FIG. 20 indicates that there is decrease in percentage viability ofspheres of PC3 in presence of compound of Formula IX compared tostandard chemotherapeutic drug Cisplatin.

FIG. 21 . Shows that compound of Formula X exhibits higher anticanceractivity on MCF7, MDMB231, PC3, DU145 cell lines compared to standardchemo therapeutic drug Cisplatin in MTT assay.

FIG. 22 . Shows that compound of Formula X exhibits higher anticanceractivity on MDMB231, PC3 cell lines compared to standardchemotherapeutic drug Cisplatin in Soft Agar Assay.

FIG. 23 Shows that there is decrease in percentage viability of spheresof MDAMB231 in presence of compound of Formula X compared to standardchemo therapeutic drug Cisplatin.

FIG. 24 Shows that compound of Formula XI exhibits higher anticanceractivity on MCF7, MDMB231, PC3, DU145 cell lines compared to standardchemo therapeutic drug Cisplatin in MTT Assay.

FIG. 25 Shows that compound of Formula XI exhibits higher anticanceractivity MDMB231, PC3 cell lines compared to standard chemotherapeuticdrug Cisplatin in Soft Agar Assay.

FIG. 26 Shows that compound of Formula XII exhibits higher anticanceractivity on MCF7, MDMB231, PC3, DU145 cell lines compared to standardchemo therapeutic drug Cisplatin in MTT Assay

FIG. 27 Shows that compound of Formula XII exhibits higher anticanceractivity on MDMB231. PC3 cell lines compared to standardchemotherapeutic drug Cisplatin in Soft Agar Assay.

FIG. 28 Shows that percentage viability of spheres of MDAMB231 inpresence of compound of Formula XII is similar compared to standardchemo therapeutic drug Cisplatin.

FIG. 29 Shows that percentage viability of spheres of PC3 in presencecompound of Formula XII is higher compared to standard chemotherapeuticdrug Cisplatin.

FIG. 30 Shows that compound of Formula XIII exhibits higher anticanceractivity on MDMB231, PC3, DU145 cell lines compared to standard chemotherapeutic drug Cisplatin in MTT assay

FIG. 31 Shows that compound of Formula XIII exhibits higher anticanceractivity on MDMB231, PC3 cell lines compared to standardchemotherapeutic drug Cisplatin in Soft Agar Assay.

FIG. 32 Shows there is decrease in percentage viability of spheres ofMDAMB231 in presence of compound of Formula XIII compared to standardchemo therapeutic drug Cisplatin.

FIG. 33 Shows that there is decrease in percentage viability of spheresof PC3 in presence of compound of Formula XIII compared to standardchemotherapeutic drug Cisplatin.

FIG. 34 . Shows that compound of Formula XIV exhibits higher anticanceractivity on MDMB231 cell line compared to standard chemo therapeuticdrug Cisplatin in Soft Agar Assay.

FIG. 35 Shows that there is decrease in percentage viability of spheresof MDAMB231 in presence of compound of Formula XIV compared to standardchemotherapeutic drug Cisplatm.

FIG. 36 Shows that there is decrease in percentage viability of spheresof PC3 in presence of compound of Formula XIV compared to standardchemotherapeutic drug Cisplatin.

DESCRIPTION OF THE INVENTION

The present invention relates to compounds for treating variousconditions, particularly for inhibition, of uncontrolled cellproliferation. Particularly the compounds are effective against cancerstem cells and treating cancer.

The present invention relates to compound of Formula 1:

wherein, R¹ is selected from —H, —CH₂OH; R² is selected from —H, alkoxy,alkyl, acetyl, C₃-C₈ acyl group; R³ is selected from alkoxy, alkyl,acetyl, C₃-C₈ acyl group; R⁴ is selected from —OH, F, —NH₂, —NHCOCH₃,alkyl, acetyl, C₃-C₈ acyl group; R⁵ is H, Cl; R⁶ and R⁷ eachindependently is selected from H, alkyl, substituted or unsubstitutedaromatic group, alkoxy, NH₂, NO₂, —NHCOCH₃, —CN, —O—, halogen, —OCF₃ orR⁶ and R⁷ together form a heterocyclic ring; R⁸ is H, Cl; R⁹ is selectedfrom a substituted or unsubstituted 5- or 6-membered ring,—CH₂—O—CH₂—COOH R¹⁰ is ═O or H; A is O, —NH, —N-alkyl; Q is O, S,—CH₂O—; X is selected from CH₂, O, N, S; E is selected from CH, O, N, S;and Z is selected from CH, O, N, S. In one embodiment, the R⁹ group is

In another embodiment of the present invention, a compound of formula IIis provided:

In an embodiment, the present invention provides compounds of FormulaIII or salts thereof for treating various conditions, particularly forinhibition of uncontrolled cell proliferation. Particularly, thecompounds are effective against cancer stem cells.

wherein, E and Z is selected from C, O, N, S, salts of N such as N. HCl;Q is O, S, —CH₂O—, wherein Y′ is selected from —H, alkyl; SOOCH3; R⁵ is—H, —Cl, when E and/or Z is —C; R⁶ and R⁷ each independently is selectedfrom —H, alkoxy, alkyl, substituted or unsubstituted aromatic group,—NH₂, —NO₂, —NHCOCH₃, —CN, —O—, halogen, —OCF₃ or R⁶ and R⁷ togetherform a heterocyclic ring; R⁸ is —H, —Cl, when E and/or Z is —C; R₉ is—CH2-O—CH2, —COOH, —X where X can be F, Cl, Br, alkyl such as —CH₃, —OH,alkoxy such as —OMe, NHCOCH₃, H, NH₂; R¹¹ and R¹² each independently isselected from —H. R¹¹ and R¹² can be substituted or unsubstituted 5- or6-membered ring such as lactone, —C(O)O-alkyl such as —C(O)OC₂H₅; R isselected from:

—II, —C(O)CH₂Cl, —SOO—CH₃, —SOOPh, —CH₂C(O)N(CH₃)₂, —C(O)NHPh,—C(O)NHPhOH, —C(S)NHPh, —CH₂Ph, —COAr, —SOOAr, —CONHAr, —CH₂Ar, —CSNHAr,wherein, R¹³ is selected from —OH, —NH₂, —NHCOCH₃, X═F, Cl, Br, alkyl,acetyl, C₃-C₈ acyl group; R¹⁴ is, selected from alkoxy, —OMe, —OH, NH₂,—NHCOCH₃, X═F, Cl, Br, alkyl, acetyl, C₃-C₈ acyl group; R¹⁵ is selectedfrom alkoxy, —OMe, —OH, —H, Br, NH₂, N═F, Cl, Br alkyl, acetyl, C₃-C₅acyl group; R¹⁶ is selected from —H, —CH₂OH, —OH, alkyl, alkoxy; R¹⁷ isselected from alkyl. According to an embodiment of the presentinvention, a compound of Formula IV or salts thereof is provided toprevent cell proliferation:

wherein, R, R⁶, R⁷, R¹¹ and R¹² have the meaning as assigned above. In apreferred embodiment of the present invention, a compound of Formula Vor salts thereof is provided to prevent cell proliferation:

The compound of Formula V of the present invention are active on Breastand prostate cancer cell lines. Further, compound of Formula V is potentcompared to standard chemotherapeutic drug Cisplatin. The compound ofFormula V does not show activity on normal lymphocytes.

In another preferred embodiment of the present invention, a compound ofFormula VI or salts thereof is provided to prevent cell proliferation:

Compound of Formula VI shows activity in breast and prostate cancer celllines. Further, compound of Formula VI is potent compared to standardchemotherapeutic drug Cisplatin. The compound of Formula VI does notshow activity on normal lymphocytes.

In an embodiment, the present invention provides compounds thatdemonstrate anticancer and anti-cancer stem cell activity particularlyin breast and prostate cancer cell lines. In an embodiment, compound offormula VII is provided:

Compound of Formula VII shows activity in breast and prostate cancercell lines. The compound of Formula VII does not show activity on normallymphocytes.

In another embodiment, the present invention provides compound ofFormula VIII that prevents cell proliferation.

Compound of Formula VIII shows activity in breast and prostate cancercell lines and does not show activity on normal lymphocytes.

In a further embodiment of the present invention compound of Formula IXis provided that prevents cell proliferation:

Compound IX of the present invention shows activity in breast andprostate cancer cell lines.

In yet another embodiment of the present invention, compound of FormulaX is provided that prevents cell proliferation:

Compound of formula X shows activity in breast and prostate cancer celllines and does not show activity in normal lymphocytes.

In yet another embodiment, the present invention provides compound ofFormula XI that prevents cell proliferation:

Compound of formula XI shows activity in breast and prostate cancer celllines

In yet another embodiment, the present invention provides compound ofFormula XII that prevents cell proliferation:

Compound of formula XII shows activity in breast and prostate cancercell lines. In a further embodiment, the present invention providescompound of Formula XIII that prevents cell proliferation:

Compound of formula XIII shows activity in breast and prostate cancercell lines.

In a further aspect, a compound of Formula XIV is provided:

Compound of formula XIV shows activity in breast cancer cell lines

In an embodiment of the present invention, compounds of formula V to XIVof the present invention for use in the treatment of cancer is provided.Preferably, the compound of Formula V and VI are provided for use in thetreatment of cancer. The cancer can be the cancer is breast, oral,prostate, brain, blood, bone marrow, liver, pancreas, skin, kidney,colon, ovary, lung, testicle, penis, thyroid, parathyroid, pituitary,thymus, retina, uvea, conjunctiva, spleen, head, neck, trachea, gallbladder, rectum, salivary gland, adrenal gland, throat, esophagus, lymphnodes, sweat glands, sebaceous glands, muscle, heart, or stomach cancer.In a preferred embodiment, the compounds of Formula V and VI for use inthe treatment of breast and/or prostate cancer is provided.

In a further embodiment, pharmaceutical compositions including thecompounds of the present invention, pharmaceutically acceptableexcipient including carrier, adjuvant, vehicle or mixtures thereof areprovided. Preferably, pharmaceutical compositions including compounds ofFormula V and VI pharmaceutically acceptable excipient includingcarrier, adjuvant, vehicle or mixtures thereof are provided. Thepharmaceutical excipient can further include one or more binders,diluents, disintegrants, glidants, lubricants, stabilizers, surfaceactive agents or pH-adjusting agents.

In certain embodiments, the amount of compound in compositions may besuch that it is effective to treat cancer in a subject in the needthereof. In certain embodiments, the composition may comprise betweenthe biologically effective dose and the maximum tolerated dose of thecompound of the invention or it's pharmaceutically acceptable salt,ester, or salt of an ester.

In certain embodiments, a composition of this invention may beformulated for administration to a subject in the need thereof. Thepharmaceutical compositions of the present invention may be formulatedinto a suitable dosage form to be administered orally, parenterally, byinhalation spray, topically, rectally, nasally, buccally, vaginally orvia an implanted reservoir. Compositions of the present invention may beformulated into dosage forms including liquid, solid, and semisoliddosage forms. The term “parenteral” as used herein includessubcutaneous, intravenous, intraperitoneal, intramuscular,intra-articular, intrasynovial, intrastemal, intrathecal, intrahepatic,intralesional and intracranial injection or infusion techniques.Preferably, the compositions are administered orally, intravenously orintraperitoneally.

The present invention also includes the composition including thecompounds of the present invention of Formula V to XIV, preferablycompound of Formula V or VI for use in the treatment of cancer includingcancer is breast, oral, prostate, brain, blood, bone marrow, liver,pancreas, skin, kidney, colon, ovary, lung, testicle, penis, thyroid,parathyroid, pituitary, thymus, retina, uvea, conjunctiva, spleen, head,neck, trachea, gall bladder, rectum, salivary gland, adrenal gland,throat, esophagus, lymph nodes, sweat glands, sebaceous glands, muscle,heart, or stomach cancer. In a preferred embodiment, the composition ofthe present invention is for the treatment of breast, and/or prostatecancer.

In certain embodiments of the present invention disclose a formulationcomprising the compounds of the present invention along with otheractive agents or pharmaceutically acceptable excipients, etc.

In an embodiment, a pharmaceutical composition comprises the aforesaidcompounds with another active agent such as but are not limited toimatinib, nilotinib, gefitinib, sunitinib, carfilzomib, salinosporamideA, retinoic acid, cisplatin, carboplatin, oxaliplatin, mechlorethamine,cyclophosphamide, chlorambucil, ifosfamide, azathioprine,mercaptopurine, doxifluridine, fluorouracil, gemcitabine, methotrexate,tioguanine, vincristine, vinblastine, vinorclbine, vindesine,podophyllotoxin, etoposide, teniposide, tafluposide, paclitaxel,docetaxel, irinotecan, topotecan, amsacrine, actinomycin, doxorubicin,daunorubicin, valrubicin, idarubicin, epirubicin, plicamycin, mitomycin,mitoxantrone, melphalan, busulfan, capecitabine, pemetrexed,epothilones, 13-cis-Retinoic Acid, 2-CdA, 2-Chlorodeoxyadenosine,5-Azacitidine, 5-Fluorouracil, 5-FU, 6-Mercaptopurine, 6-MP, 6-TG,6-Thioguanine, Abraxane, Accutane, Actinomycin-D, Adriamycin, Adrucil,Afinitor, Agrylin, Ala-Cort, Aldesleukin, Alemtuzumab, ALIMTA,Alitretinoin, Alkaban-AQ, Alkeran, All-transretinoic Acid, AlphaInterferon, Altretamine, Amethopterin, Amifostine, Aminoglutethimide,Anagrelide, Anandron, Anastrozole, Arabinosylcytosine, Ara-C, Aranesp,Aredia, Arimidex, Aromasin, Arranon, Arsenic Trioxide, Arzerra,Asparaginase, ATRA, Avastin, Azacitidine, BCG, BCNU, Bendamustine,Bevacizumab, Bexarotene, BEXXAR, Bicalutamide, BiCNU Aromasin,Blenoxane. Bleomycin, Bortezomib, Busulfan, Busulfex, C225, CalciumLeucovorin, Campath, Camptosar, Camptothecin-11, Capecitabine, Carac,Carboplatin, Carmustine, Carmustine Wafer, Casodex, CC-5013, CCI-779,CCNU, CDDP, CeeNU, Cerubidine, Cetuximab, Chlorambucil, CitrovorumFactor, Cladribine, Cortisone, Cosmegen, CPT-11, Cytadren, Cytosar-U,Cytoxan, Dacarbazine, Dacogen, Dactinomycin, Darbepoetin Alfa,Dasatinib, Daunomycin, Daunorubicin Hydrochloride, DaunorubicinLiposomal, DaunoXome, Decadron, Decitabine, Delta-Cortef, Deltasone,Denileukin, Diftitox, DepoCyt, Dexamethasone, Dexamethasone Acetate,Dexamethasone Sodium Phosphate, Dexasone, Dexrazoxane, DHAD, DIC,Diodex, Docetaxel, Doxil, Doxorubicin, Doxorubicin Liposomal, Droxia,DTIC, DTIC-Dome, Duralone, Efudex, Eligard, Ellence, Eloxatin, Elspar,Emcyt, Epirubicin, Epoetin Alfa, Erbitux, Erlotinib, ErwiniaL-asparaginase, Estramustine, Ethyol, Etopophos, Etoposide, EtoposidePhosphate, Eulexin, Everolimus, E vista, Exemestane, Fareston, Faslodex,Femara, Filgrastim, Floxuridine, Fludara, Fludarabine, Fluoroplex,Fluorouracil, Fluorouracil (cream), Fluoxymesterone, Flutamide, FolinicAcid, FUDR, Fulvestrant, G-CSF, Gefitinib, Gemcitabine, Gemtuzumab,ozogamicin, Gemzar Gleevec, Gliadel Wafer, GM-CSF, Goserelin,Granulocyte—Colony Stimulating Factor, Granulocyte Macrophage ColonyStimulating Factor, Halotestin, Herceptin, Hexadrol, Hexalen,Hexamethylmelamine, HMM, Hycamtin, Hydrea, Hydrocort Acetate,Hydrocortisone, Hydrocortisone Sodium Phosphate, Hydrocortisone SodiumSuccinate, Hydrocortone Phosphate, Hydroxyurea, Ibritumomab, Tiuxetan,Idamycin, Idarubicin Ifex, IFN-alpha, Ifosfamide, IL-11, IL-2, Imatinibmesylate, Imidazole Carboxamide, Interferon alfa, Interferon Alfa-2b(PEG Conjugate), Interleukin-2, Interleukin-11, Intron A (interferonalfa-2b), Iressa, Irinotecan, Isotretinoin, Ixabepilone, Ixempra,Kidrolase, Lanacort, Lapatinib, L-asparaginase, LCR, Lenalidomide,Letrozole, Leucovorin, Leukeran, Leukine, Leuprolide, Leurocristine,Leustatin, Liposomal Ara-C, Liquid Pred, Lomustine, L-PAM, L-Sarcolysin,Lupron, Lupron Depot, Matulane, Maxidex, Mechlorethamine,Mechlorethamine Hydrochloride, Medralone, Medrol, Megace Megestrol,Megestrol Acetate, Melphalan, Mercaptopurine, Mesna, Mesnex,Methotrexate, Methotrexate Sodium, Methylprednisolone, Meticorten,Mitomycin, Mitomycin-C, Mitoxantrone, MTC, MTX, Mustargen, Mustine,Mutamycin, Myleran, Mylocel, Mylotarg, Navelbine, Nelarabine, Neosar,Neulasta, Neumega, Neupogen, Nexavar, Nilandron, Nilotinib, Nilutamide,Nipent, Nitrogen Mustard, Novaldex, Novantrone, Nplate, Octreotide,Octreotide acetate, Ofatumumab, Oncospar, Oncovin, Ontak, Onxal,Oprelvekin, Orapred, Orasone, Oxaliplatin, Paclitaxel, PaclitaxelProtein-bound, Pamidronate, Panitumumab, Panretin, Paraplatin,Pazopanib, Pediapred, PEG Interferon, Pegaspargase, Pegfilgrastim,PEG-INTRON, PEG-L-asparaginase, PEMETREXED, Pentostatin, PhenylalanineMustard, Platinol, Platinol-AQ, Prednisolone, Prednisone, Prelone,Procarbazine, PROCRIT, Proleukin, Prolifeprospan 20 with CarmustineImplant, Purinethol, Raloxifene, Revlimid, Rheumatrex, Rituxan,Rituximab, Roferon-A (Interferon Alfa-2a), Romiplostim, Rubex,Rubidomycin hydrochloride, Sandostatin, Sandostatin LAR, Sargramostim,Solu-Cortef, Solu-Medrol, Sorafenib, SPRYCEL, STI-571, Streptozocin,SU11248, Sunitinib, Sutent, Tamoxifen, Tarceva, Targetin, Tasigna,Taxol, Taxotere, Temodar, Temozolomide, Temsirolimus, Teniposide, TESPA,Thalidomide, Thalomid, TheraCys, Thioguanine, Thioguanine Tabloid,Thiophosphoamide, Thioplex, Thiotepa, TICE, Toposar, Topotecan,Toremifene, Torisel, Tositumomab, Trastuzumab, Treanda, Tretinoin,Trexall, Trisenox, TSPA, TYKERB, VCR, Vectibix, Velban, Velcade,VePesid, Vesanoid, Viadur, Vidaza, Vinblastine, Vinblastine Sulfate,Vincasar Pfs, Vincristine, Vinorelbine, Vinorelbine tartrate, VLB,VM-26, Vorinostat, Votrient, VP-16, Vumon, Xeloda, Zanosar, Zevalin,Zinecard, Zoladcx, Zoledronic acid, Zolinza, Zometa, or combinations ofany of the above.

In yet another embodiment, a method of treating cancer by administeringan effective amount of compounds V to XIV of present invention isprovided. In a preferred embodiment, a method of treating cancercomprising administering an effective amount of compound of formula V orVI is provided. The cancer can be breast, oral, prostate, brain, blood,bone marrow, liver, pancreas, skin, kidney, colon, ovary, lung,testicle, penis, thyroid, parathyroid, pituitary, thymus, retina, uvea,conjunctiva, spleen, head, neck, trachea, gall bladder, rectum, salivarygland, adrenal gland, throat, esophagus, lymph nodes, sweat glands,sebaceous glands, muscle, heart, or stomach cancer. In a preferredembodiment, the method of treatment of the present invention comprisingadministering an effective amount of compound of Formula V or VI can befor the treatment of breast and/or prostate cancer.

In an embodiment, a method of inhibition of unregulated cell growth byadministering effective amount of the compounds of the present inventionis provided.

In a further embodiment, the method of treating cancer by administeringcompounds of the present invention along with standard therapies or incombination with other drugs available for the treatment of cancer.

Another embodiment of the invention provides for the use of thecompounds in the treatment of unregulated cell growth, malaria, dengue.

The foregoing description of the invention has been set merely toillustrate the invention and is not intended to be limiting. Sincemodifications of the disclosed embodiments incorporating the spirit andsubstance of the invention may occur to person skilled in the art, theinvention should be construed to include everything within the scope ofthe disclosure. Following are the illustrative and non-limitingexamples, including the best mode, for practicing the present invention.

Example 1

Synthetic Scheme for Diphyllin Derivatives

Procedure:

Synthesis of 2:

Substituted aromatic aldehyde (0.3 mole) was taken in AcOH (200 mL) andBr₂ (0.6 mole) was added slowly from addition funnel. The mixture wasstirred for 3 h at room temperature and then poured over ice (100 g) andstirred vigorously for 30 min. Slurry was filtered and residue waswashed with cold methanol and suction dried under vacuum to obtain pureproduct 2. Yield, 0.25 mole (85%).

Synthesis of 3:

Compound 2 (0.11 mole) was dispersed in 350 mL of toluene. Ethyleneglycol 70 mL and p-Toluenesulphonic acid (0.5 g) were added and mixturewas refluxed using Dean-stark assembly for 5 h. Reaction was monitoredwith TLC (3:7, Ethyl acetate:Hexane). After completion of reaction,saturated NaHCO₃ solution was added into the reaction and layers wereseparated. Toluene layer was washed with brine and dried over anhydrousNa2SO4. Dried toluene layer was evaporated in vacuum to afford pureproduct 3 (0.11 mole, 97%).

Synthesis of 4:

In an inert reaction assembly charged with nitrogen compound 3 (0.034mole) was dissolved in Dry THF (150 mL). Mixture was then cooled in adry ice/acetone bath till −65° C. Through transfer needle 50 ml n-BuLi(1.6M solution in hexane) was added carefully and slowly into the abovesolution over 30 min. Mixture was stirred for 1 h at −65° C. In aseparate addition funnel, the solution of R⁶—CHO in THF was added dropwise in to the lithiated solution at −65° C. Mixture was stirred for 30min at same temperature and left at room temperature for 2 h. Mixturewas quenched with 10 mL sat. NH₄Cl solution and extracted with ethylacetate (200 mL×2). Ethyl acetate layer was washed with brine solution(100 mL×2), dried over anhydrous Na₂SO₄ and evaporated in vacuum toisolate crude product. Purification by column chromatography (in silicagel, Ethyl acetate:hexane) gave pure product 4 (0.008 mole, 24%).

Synthesis of 5:

Compound 4 (0.012 mole), acetic acid (6.7 mL), DEADC (0.016 mole) andMDC (100 mL) were taken into the high pressure closed vessel. Mixturewas heated at 140° C. for 2 h. Heating stopped and mixture was washedwith saturated NaHCO₃. MDC layer was dried with anhydrous Na₂SO₄ andsolvents were evaporated in vacuum and crude product was purified bysilica gel column chromatography in ethyl acetate:hexane as a mobilephase. Pure product 5 obtained as an off white solid (0.016 mole, 93%).

Synthesis of 6:

Ester 5 (0.0021 mole) was dissolved in dry THF and slowly added into thedispersion of LiAlH₄ (0.0042 mole) in THF at 0° C. Mixture was stirredat 0° C. for 2 h and then at room temperature for overnight. Reactionwas quenched with saturated NH₄Cl and product was extracted with MDC.Crude product was purified by column chromatography to obtain pureproduct 6 (0.0011 mole).

Synthesis of Glycoside Portion

Synthesis of tetra-acylated d-xylose (7):

D-xylose (0.13 mole) was mixed in MDC (100 mL) and pyridine at roomtemperature. Mixture cooled to 0° C. and acetyl chloride (0.78 mole) wasadded slowly under vigorous stirring. Mixture stirred for 1 h at 0° andthen at room temperature for 3 h. 50 gm crushed ice was added into themixture and then 200 mL MDC. Layers were separated and MDC extract waswashed with brine solution (100 mL×2) and 10% aq. CuSO₄ solution untiloriginal CuSO4 solution color persists. MDC layer was dried overanhydrous Na₂SO₄ and evaporated in vacuum on rotary evaporator to obtainthe syrupy product 7 (0.129 mole, 97%).

Synthesis of 8:

In a clean and dry round bottom flask, with nitrogen inlet, compound 7(0.129 mole) was dissolved in 200 mL dry MDC. Mixture cooled to 0° C. inan ice bath and 100 mL HBr/AcOH (33% solution) was added drop wise overa period of 30 min. Material stirred for 2 h at 0° C. and quenched with50 g ice and stirred for 10 min. MDC layer was separated and washed withsat. NaHCO₃ (100 mL×3), brine (100 mL) and dried over anhydrous Na₂SO₄and evaporated in vacuum on rotary evaporator to obtain the off-whitesolid product 8 (0.097 mole, 76%).

Synthesis of 9:

Above compound 8 was taken directly into another round bottom flaskcontaining TBAB (0.040 mole), 2, 6-Lutidine (0.129 mole) and MDC 200 mLand stirred at room temperature for 1 h. After 1 h stirring 6.5 mL EtOHwas added slowly and stirring continued for overnight. Solvent removedon rotary evaporator and residue triturated in ethyl acetate (200 mL).Solids were removed by filtration and filtrate was evaporated. Syrupycrude product was purified by silica gel column chromatography in ethylacetate:hexane to obtain semisolid pure product 9 (0.049 mole, 51%).

Synthesis of 10:

In a single neck round bottom flask compound 9 (0.049 mole) wasdissolved in MeOH at room temperature. This mixture cooled between15-10° C. and NaOMe (600 mg) was added in small portions over 10 min andthen stirred for 2 h at room temperature. Thin Later Chromatography(TLC) confirmed the de-acylated product formation. Methanol evaporatedon rotary evaporator and residue was dissolved in dry DMF (100 mL). DMFsolution chilled to 0° C. and NaH (6 g, 60% suspension) was addedportion wise under vigorous stirring under nitrogen atmosphere.Suspension stirred for 15 min at same temperature and methyl iodide wasadded slowly. Whole suspension was stirred overnight at RT. When TLCconfirmed the product formation, 2 mL MeOH and crushed ice, (150 g) wereadded slowly. Reaction mixture was extracted with ethyl acetate (200mL×2). Combined ethyl acetate extract was washed with saturated brinesolution (50 mL×4) dried over an. Na2SO4 and evaporated on rotaryevaporator to obtain oily liquid product 10 (0.048 mole, 98%).

Synthesis of 11:

Compound 10 (0.048 mole) was dissolved in gl. AcOH (50 mL) at 0° C. andstirred for 1 h at room temperature. Acetic acid was evaporated andobtained syrupy residue was dissolved in pyridine (100 mL) and cooled upto 0° C. Ac—Cl was slowly charged into the chilled solution and stirredat room temperature for overnight. Into the reaction mixture 50 mLchilled water was added and extracted with diethyl ether (100 ml×2).Ether extract was washed with sat. CuSO₄ solution (50 ml×4) and brine(50 ml) dried over An. Na₂SO₄ and evaporated on rotary evaporator toisolate product 11 (0.038 mole, 79%)

Synthesis of 12:

In 100 ml dry MDC 11 (0.015 mole) was added and chilled up to 0° C. 10mL HBr/AcOH (33% solution) was added slowly and mixture was stirred for1 h at 0° C. Crushed ice (20 g) was added in to the reaction stirred for5 min. MDC layer was washed with sat. NaHCO₃ solution (50 mL×4), brine(50 ml) and dried over Na₂SO₄ and resulting solution used as such forthe synthesis of 13 (see scheme III).

Coupling of Diphyllin Derivative (6) and Glycoside Moiety (12)

Synthesis of 13:

Diphyllin derivative (6, 0.0065 mole), TBAB (0.006 mole) and 2N NaOH (25mL) were mixed in MDC (50 mL) at 0° C. To this, above prepared solutionof 13 in MDC was added slowly. Reaction was stirred for 1.5 h and TLCconfirmed the product formation. Into the reaction, 25 mL ice cold waterwas added and stirred vigorously, and then organic phase was separated.MDC layer was washed with 2N NaOH, water, brine and dried over Na₂SO₄,evaporated on rotary evaporator to obtain crude 13 (2.3 g). Crudeproduct was purified by silica gel column chromatography in Ethylacetate:Hexane from which pure compound 13 (0.0020 mole) was isolated.

Synthesis of 14:

Condensation product 13 (0.0020 mole) from Glycoside and diphyllinderivative was dissolved in MeOH and chilled the solution till 0°. Tothis solution anhydrous K₂CO₃ was added and stirred for 1 h at roomtemperature. TLC shows complete conversion of 13 into the product 14.Aq. HCl (1N) was added to adjust the neutral pH and MDC was added toextract the product. MDC layer was washed with brine and dried overNa₂SO₄ and evaporation of MDC on rotary evaporator afforded crudeproduct, which was purified by silica gel column chromatography in Ethylacetate:Hexane. Pure product 14 (0.00092 mole, 46%) was obtainedwith >98% purity.

Example 2

Synthesis of Compound of Formula V (Numbered as 14 in Scheme 3)

Step I: Synthesis of 4-(benzo[d][1,3]dioxol-5-yl)naphthalen-1-ol

Experiments

Synthesis of 4-bromonaphthalen-1-ol (2)

To a solution of 1 (5 g, 34.7 mmol) in 180 mL of ACN, NBS (6.18 g, 34.7mmol); as added over a period of 1 hr. The reaction mixture was stirredat RT for additional 30 min and monitored using TLC. The solvent wasevaporated and the residue was partitioned I; n diethyl ether and water.The ethereal layer was dried over anhydrous sodium sulfate andconcentrated reduces pressure.

Synthesis of 1-(benzyloxy)-4-bromonaphthalene (3)

To a solution of 2 (7 g, 31.4 mmol) in DMF, K₂, CO₃ (8.9 g, 64.44 mmol)was added followed by slow-addition of benzyl bromide (3.98 mL, 33.5mmol). The reaction mixture was stirred at RT and monitored using TLC.After completion, reaction was quenched with brine and the residue wasextracted using ethyl acetate and washed with water. The combinedorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The obtained solid was purified by columnchromatography (Hex:EtOAc, 98:2).

Synthesis of 5-(4-(benzyloxy)naphthalen-1-yl)benzo[d][1,3]dioxole (4)

To a solution of 3 (1 g, 3.2 mmol) in DME, Pd(PPh₃)₄ (0.184 g, 5 mol %)was added and stirred for 30 min at RT. The suspension of3,4-(methylenedioxy)phenylboronic acid (0.635 g, 3.82 mmol) in DME wasadded to the above solution followed by addition of 2M Na₂CO₃ (0.676 g)solution. The reaction mixture was refluxed overnight, and monitoredusing TLC after completion, cooled to RT and solvent was distilled off.The residue was treated with aq. NH₄Cl solution and extracted in ethylacetate. The combined organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The obtained solid waspurified by column chromatography (Hexane:DCM, 95:5)

Synthesis of 4-(benzo[d][1,3]dioxol-5-yl)naphthalen-1-ol (5)

A mixture of 4 (1 g, 2.82 mmol), 10% Pd/C in 50 mL of mixture ofEtOH:EtOAc (1:1) was placed in shaker hydrogenation apparatus at 60° C.and 60-80 psi. The reaction was monitored using TLC. After completion,Pd/C was filtered off and the filtrate was evaporated. The obtainedsolid was purified by column chromatography (DCM:MeOH, 99:1)

Step II: Synthesis of 2-O-Acetyl-3,4-dimethoxy-α-D-bromoxylopyranose(12)

Synthesis of Tetra-O-acetyl-D-xylopyranose (7)

To a 500-mL three-neck RBF equipped with guard-tube and stopper, wereadded 6 (40.0 g. 0.266 mol), pyridine (200 mL) and cooled at 0° C.Acetic anhydride (200 mL) was added dropwise to the above mixture at 0°C. The resulting reaction mixture was stirred at 0° C. for 5 h. Afterconsumption of starting materials, as judged by TLC (5:5, EtOAc:Hexane),reaction mixture was poured into ice water (500 mL) and ether was added(200 mL). Organic layer was separated, and aqueous layer was extractedwith ether (2×250 mL). Organic layers were combined and washed withsaturated cupric salt solution till free from pyridine. The organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedto give sticky solid compound 7.

¹H-NMR (300 MHz, CDCl₃): δ=6.27 (d, 1H, J=3.6 Hz), 5.70 (t, 1H, J=9 Hz),5.06 (m, 2H), 3.97 (dd, 1H, J=6.0, 1 1.1 Hz), 3.72 (t, 1H, J=1 1.0 Hz),2.18 (s, 3H), 2.07 (s, 6H), 2.03 (s, 3H).

Synthesis of 2,3,4-Tri-O-acetyl-a-D-bromoxylopyranose (8)

1 L-RBF with guard tube was charged with 7 (25.0 g, 78.54 mol) anddichloromethane (500 mL) and the mixture was cooled to 0° C. in icebath. To the above cold solution was added hydrogen bromide (33% inacetic acid; 56 mL) with constant stirring during 1 h and reactionmixture was further stirred at room temperature for 1 h. Aftercompletion of reaction as judged by TLC (4:6, EtOAc:Hexane), reactionmixture was washed with ice water (1×500 mL), 1% NaHCO₃ solution (1×500mL), 10% NaHCO₃ solution (2×500 mL) and finally by brine solution (1×500mL). Organic layer was dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to obtained white solid of 8.

¹H-NMR (300 MHz, CDCl₃): δ=6.59 (d, 1H, J=3.9 Hz), 5.60 (t, 1H, J=9.9Hz), 5.05-5.03 (m, 1H), 4.77 (dd, 1H, J=3.9, 9.6 Hz), 4.07 (dd, 1H,J=6.3, 11.4 Hz), 3.88 (t, 1H, J=11.1 Hz), 2.10 (s, 3H), 2.06 (s, 6H).

Synthesis of 3,4-Di-O-acetyl-1,2-O-(l-ethoxyethylidene)-D-xylopyranose(9)

1. Two necked RBF were charged with 8 (25.0 g, 73.71 mmol), 2,6-lutidine(11.07 mL, 95.82 mmol), tetrabutyl ammonium bromide (9.50 g, 29.48 mmol)and anhydrous dichloromethane (147 mL). To the above mixture was addedabsolute ethanol (4.7 mL, 81.08 mmol) and reaction mixture was stirredat room temperature under nitrogen atmosphere for overnight. Aftercompletion of reaction as judged by TLC (5:5, EtOAc:Hexane), thereaction mixture was concentrated under reduced pressure. The residuewas purified by column chromatography over silica gel using EtOAc:Hexaneas eluent to afford 9 as a pale yellow colored liquid.

¹H-NMR (300 MHz, CDCl3): δ=5.57 (d, 1H, J=4.2 Hz), 5.24 (t, 1H, J=3.6Hz), 4.84-4.82 (m, 1H), 4.20 (t, 1H J=1.8 Hz), 3.89 (dd, 1H, J=5.1, 12.3Hz), 3.71 (dd, III, J=6.9, 12.3 Hz), 3.59 (q, 2H, J=6.9 Hz), 2.10 (s,311), 2.08 (s, 3H), 1.19 (t, 3H, J=6.9 Hz).

2. In a dried RBF (250 mL) was charged with 9 (10 g, 32.86 mmol) andanhydrous methanol (157 mL) was added. To the above solution was addedcatalytic amount of sodium methoxide (300 mg) and stirred at roomtemperature for 1 h. After the completion of reaction as judged by TLC,reaction mixture was concentrated under reduced pressure and residue wasdried under high vacuum. The resulting residue was dissolved inanhydrous DMF (100 mL) and cooled to 0° C. in ice-bath. To the abovecold solution, sodium hydride (3.94 g, 60% dispersion in oil. 164.3mmol) was added and resulting suspension was with stirring for 1 h.Methyl iodide (12.4 mL, 197.6 mmol) was added dropwise at 0° C., thereaction mixture was then slowly brought to room temperature during 1 hand further stirred at room temperature for 12 h. After completion ofreaction, reaction was quenched by addition of methanol (10 mL), dilutedwith ethyl acetate (100 mL), washed with water (2×50 mL), brine solution(1×50 mL) and dried over anhydrous sodium sulfate. The inorganic saltswere filtered off, filtrate was concentrated under reduced pressure andresidue was purified by column chromatography using EtOAc:Hexane (10:90)to afford 10 as a light yellow colored liquid.

¹H-NMR (300 MHz, CDCl3): δ=5.56 (d, 1H, J=4.8 Hz), 4.29-4.26 (m, 1H),3.89 (dd. 1H J=3.3, 12.1 Hz), 3.82-3.69 (m, 5H), 3.54 (s, 3H), 3.44 (s,3H), 3.26 (m, 1H), 1.19 (t, 3H, 6.9 Hz).

Synthesis of 1,2-Di-0-acetyl-3,4-dimethoxy-D-xylopyranose (11)

10 (7.5 g, 30.20 mmol) was dissolved in acetic acid (55 mL) andresulting solution was stirred at 0° C. for 1 h. Reaction mixture wasconcentrated under reduced pressure and the residue was treated withacetic anhydride (26 mL) and pyridine (26 mL). The resulting solutionwas maintained at room temperature with stirring for overnight. Aftercompletion of reaction as judged by TLC (3:7, EtOAc:Hexane), reactionmixture was poured into cold water (100 mL) and extracted with ether(4×100 mL). The organic layers were combined, washed with saturatedcupric sulfate solution till the pyridine was removed and then driedover anhydrous sodium sulfate. The inorganic solids were filtered off,filtrate was concentrated under reduced pressure and residue waspurified by column chromatography over silica gel using EtOAc:Hexane(20:80) as eluent to afford 11 as a light yellow color.

¹H-NMR (300 MHz, CDCl3): δ=5.62 (d, 1H, J=12 Hz), 4.95 (t, 1H J=7.8 Hz),4.1 1 (m, 1H), 3.57 (s, 3H), 3.48 (s, 3H), 3.39-3.31 (m, 3H), 2.10 (s,3H), 2.09 (s, 3H).

Synthesis of 2-O-Acetyl-3,4-dimethoxy-α-D-bromoxylopyranose (12)

In a clean and dry 50 mL RBF, 11 (1.0 g, 3.81 nmol) was dissolved indichloromethane (25 mL) and cooled to 0° C. in ice bath. To the abovecooled solution was added hydrogen bromide in AcOH (33% solution; 2.5mL) with constant stirring for 1 h and further stirred at roomtemperature for another 1 h. After completion of reaction as judged byTLC (3:7, EtOAc:Hexane), reaction mixture was diluted withdichloromethane (50 ML), washed with ice water (50 mL) followed bysaturated NaHCO₃ solution (50 mL) and finally with brine solution (50mL). Organic layer was dried over anhydrous sodium sulfate, filtered andconcentrated to give yellow colored liquid 12 as a product.

¹H-NMR (300 MHz, CDCl3): δ=6.56 (d, 1H, J=3.9 Hz), 4.56 (dd, 1H, J=3.9,9.6 Hz), 4.00 (dd, 1H, J=6.3, 1 1.7. Hz), 3.72 (m, 1H), 3.56 (s, 3H),3.54 (s, 3H), 3.38 (m, 2H), 2.13 (s, 3H).

Step III: Synthesis of(3R,4R,5R)-2-(4-(benzo[d][1,3]dioxol-5-yl)napthalen-1-yloxy)-4,5-dimethoxytetrahydro-2H-pyran-3-ol(14)

Synthesis of(3R,4R,5R)-2-(4-(benzo[d][1,3]dioxol-5-yl)naphthalen-1-yloxy)-4,5-dimethoxy-tetrahydro-2H-pyran-3-ylacetate (13)

To a 50 mL RBF, 5 (0.208 g, 0.788 mmol), 12 (0.446 g, 1.576 mmol) andtetrabutyl ammonium bromide (0.254 g, 0.788 mmol) were taken indichloromethane (20 mL) with stirring. To this suspension was added 2MNaOH (3 mL) solution and stirring was continued for 2 h at roomtemperature. After the completion of reaction as judged by TLC (1:9,EtOAc:DCM), the reaction mixture was extracted with dichloromethane(4×20 mL). The combined organic layer was washed with 10% NaOH solution(3×15 mL) followed by water (2×10 mL) and dried over anhydrous sodiumsulfate. Inorganic salts were filtered off; filtrate was concentratedunder reduced pressure and crude mass which was purified by columnchromatography using EtOAc:dichloromethane (4:96) as eluent to obtain 13as white solid.

Synthesis of(3R,4R,5R)-2-(4-(benzo[d][1,3]dioxol-5-yl)naphthalen-1-yloxy)-4,5-dimethoxy-tetrahydro-2H-pyran-3-ol(14)

To a solution of 13 (0.160 g, 0.343 mmol) in methanol (7.5 mL) was addedsolid anhydrous K₂CO₃ (0.0925 g 0.675 mmol) and reaction mixture wasstirred at room temperature for 30 min. After completion of reaction asjudged by TLC (5:5, EtOAc:Hexane), methanol was removed under reducedpressure, water was added and extracted with CH₂Cl₂ (2×25 mL). Organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedto get 14 as white fluffy solid.

% Purity: 99%; LC-MS (ESI) m/z: 425 [M+H]⁺

¹H-NMR (400 MHz, CDCl3): δ=8.35 (d, 1H, J=8 Hz), 7.89 (d, 1H, J=8 Hz),7.51-7.46 (m, 2H), 7.31 (d, 1H, J=7.6 Hz), 7.14 (d, 1H, J=8.0 Hz), 6.94(m, 3H), 6.03 (s, 2H), 5.52 (d, 1H, J=3.6 Hz), 4.18 (dd, 1H, J=6.3, 11.7. Hz), 4.05 (m, 1H), 3.69 (s, 3H), 3.61 (m, 2H), 3.51 (s, 3H), 3.45(m, 1H), 3.38 (m, 1H).

Example 3 Synthesis of Compound of Formula VI (Numbered as 26 in Scheme4) Synthesis of diethyl1-(benzo[d][1,3]dioxol-5-yl)-4-((3R,4R,5R)-3-hydroxy-4,5-dimethoxy-tetrahydro-2H-pyran-2-yloxy)-6,7-dimethoxynaphthalene-2,3-dicarboxylate(26)

Experimental:

Cleyacetate (25):

To a 50-mL round bottom flask, diethyl1-(benzo[d][1,3]dioxol-5-yl)-4-hydroxy-6,7-dimethoxynaphthalene-2,3-dicarboxylate(19; 0.30 g, 0.638 mmole),2-O-Acetyl-3,4-dimethoxy-α-D-bromoxylopyranose (12, 0.446 g, 1.276mmole) and tetrabutyl ammonium bromide (0.254 g, 0.638 mmole) were takenin dichloromethane (20 mL) with stirring. To this suspension was added2M NaOH (3 mL) solution and stirring was continued for 2 h at roomtemperature. After the completion of reaction as judged by TLC (1:9,EtOAc:DCM), the reaction mixture was extracted with dichloromethane(4×20 mL). The combined organic layer was washed with 10% NaOH solution(3×15 mL) followed by water (2×10 mL) and dried over anhydrous sodiumsulfate. Inorganic salts were filtered off filtrate was concentratedunder reduced pressure and crude mass which was purified by columnchromatography 4 using EtOAc:dichloromethane (04:96) as eluent to obtainCleyacetate (25) as an oil.

Synthesis of diethyl1-(benzo[d][1,3]dioxol-5-yl)-4-((3R,4R,5R)-3-hydroxy-4,5-dimethoxy-tetrahydro-2H-pyran-2-yloxy)-6,7-dimethoxynaphthalene-2,3-dicarboxylate(26)

To a solution of 25 (0.20 g, 0.298 mmole) in methanol (7.5 mL) was addedsolid anhydrous K₂CO₃ (0.0825 g 0.597 mmol) and reaction mixture wasstirred at room temperature for 30 min. After completion of reaction asjudged by TLC (5:5, EtOAc:Hexane), methanol was removed under reducedpressure, water was added and extracted with CH₂Cl₂ (2×25 mL). Organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedto get 26 as off white fluffy solid.

Yield: 179 mg (96%); % Purity: 99%; LC-MS (ESI) m/z: 629 [M+H]⁺

¹HNMR (CDCl3, 400 MHz): □=8.17 (s, 1H), 7.05 (d, 1H, J=1.5 Hz), 6.94(dd, 1H, J=1.2, 7.8 Hz), 6.98 (d, 2H, J=1.6 Hz), 6.92 (d, 1H, J=1.2 Hz),6.80 (d, 1H, J=8 Hz), 6.12 (s, 2H), 5.73 (m, 1H), 5.50 (q, 2H, J=3.6Hz), 5.00 (d, 1H, J=5.2 Hz), 4.80 (t, 1H, J=6.8 Hz, 4.72 (d, 1H, J=4.4Hz) 3.94 (s, 3H), 3.86-3.81 (m, 31H), 3.70 (s, 3H), 3.51 (m, 1H), 3.46(m, 1H).

Example 4 Synthesis of Compound of Formula VII (Numbered as 21 in Scheme6) and Compound of Formula VIII (Referred as 22 in Scheme 7)

Step I: Synthesis of Diphyllin

Experimental:

Synthesis of 2-Bromo-4,5-dimethoxybenzaldehyde (16)

Three necked RBF (500 mL) equipped with dropping funnel, magneticstirrer, and stopper was charged with veratraldehyde or4,5-dimethoxybenzaldehyde (15, 15 g, 0.090 mol) and acetic acid (210mL). To this solution was added bromine (9.67 mL) in acetic acid (60 mL)dropwise with constant stirring over half an hour and stirring wasfurther continued for 3 h at room temperature. During this time all thestarting materials was consumed as confirmed by TLC (3:7, EtOAc:Hexane).Water (250 mL) was added to the reaction mixture and cooled to 0° C. Theprecipitated solid was filtered off, washed with cold water and driedunder vacuum to get a white solid 16.

¹H-NMR (CDCl3, 300 MHz): δ=10.19 (s, 1H), 7.43 (s, IH), 7.07 (s, 1H),3.97 (s, 3H). 3.93 (s, 3H).

Synthesis of 2-(2-Bromo-4,5-dimethoxyphenyl)-1,3-dioxolane (17)

Three necked RBF (250 mL) was equipped with Dean-Stark apparatus andreflux condenser, was charged with 16 (19.0 g, 0.07 mol), toluene (200mL), ethylene glycol (1.8 mL, 0.21 mol) and catalytic amount ofp-toluene sulphonic acid. The reaction flask was immersed in oil bathand heated (90-95° C.) under reflux for 9 h (till all the waterremoved). After completion of reaction as judged by TLC (2:8,EtOAc:Hexane), reaction mixture was allowed to cool to room temperature,neutralized by sodium bicarbonate solution and extracted with ethylacetate (3×100 mL). All the organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The crude mass was purified by column chromatography oversilica gel using ethyl acetate (5-10%) in hexane as eluent to afford 17as a white solid.

¹H-NMR (300 MHz, CDCl3): δ=7.1 1 (s, 1H), 7.01 (s, 1H), 5.99 (s, 1H),4.18 (t, 2H, J=6.9 Hz), 4.08 (t, 2H, J=6.9 Hz), 3.89 (s, 3H), 3.88 (s,3H).

Synthesis of(2-(1,3-Dioxolan-2-yl)-4,5-dimethoxyphenyl)(benzo[d][1,3]dioxol-5-yl)-meth-anol(18)

To a flame dried three necked RBF (100 mL) were added 16 (1.0 g, 0.0034mole) and anhydrous THF (25 mL) under nitrogen atmosphere. The flask wascooling to −78° C. in dry ice-acetone bath, n-BuLi (5.3 mL, 0.005 mol)was added dropwise with stirring at −78° C. and stirred for 15 min. Aseparate flame dried flask was charged with piperonal (0.517 g, 0.0034mol) and dry THF (6 mL). The piperonal solution was cannulated to thereaction mixture during 30 min and after the addition; reaction mixturewas slowly warmed to room temperature and further stirred for 2.5 h.After the consumption of all bromo compound, as confirmed by TLC (5:5,EtOAc:Hexane), reaction mixture was quenched by the addition ofsaturated ammonium chloride solution and extracted with ethyl acetate(3×20 mL). All the organic layers were combined, dried over anhydroussodium sulfate, filtered and concentrated. The crude product waspurified by titration with heptane and 18 is sufficiently pure toproceed to next step.

¹H-NMR (300 MHz, CDCl3): δ=7.14 (s, 1H), 6.90-6.78 (m, 4H), 6.1 1 (s,1H), 5.96 (s, 2H), 5.90 (s, 1H), 4.19 (t, 2H, J=6.6 Hz), 4.16 (t, 2H,J=6.8 Hz), 4.02 (s, 3H), 3.81 (s, 3H), 3.17 (s, 1H). 13C-NMR (300 MHz,CDCl3): δ=149.42, 148.1 1, 147.57, 146.58, 136.95, 135.43, 126.83,121.04, 1 19.69, 1 1 1.48, 109.50, 107.92, 107.26, 101.65, 100.93,71.34, 65.05, 55.94, 55.89.

Synthesis of Diethyll-(3′,4′-methylenedioxypheny)-4-hydroxy-6,7-dimethoxy-naphthalene-2,3-dicarboxylate(19)

Sealed tube was charged with 18 (0.30 g, 0.833 mmol), diethylacetylinedicarboxylate (0.141 g, 0.833 mol), dichloromethane (0.4 mL)and glacial acetic acid (0.242 mL) and mixture was heated at 140° C. for1 h. After completion of reaction as judged by TLC (5:5, EtOAc:Hexane),reaction mixture was cooled to room temperature, diluted withdichloromethane (10 mL), washed with 5% sodium bicarbonate solution(3×10 mL), organic layer was dried over anhydrous sodium sulfate,filtered and concentrated. The crude reaction mass was purified by flashcolumn chromatography over silica gel using EtOAc:Hexane (15:85) toafford 19 as white solid.

¹H-NMR (300 MHz, CDCl3): δ=7.73 (s, 1H), 6.89 (d, 1H, J=7.8 Hz),6.81-6.75 (m, 3H), 6.05 (d, 2H, J=14.4 Hz), 4.44 (q, 2H. J=7.2 Hz), 4.07(q, 2H, J=6.9 Hz), 4.05 (s, 3H), 3.77 (s, 3H), 1.38 (t, 3H, J=7.2 Hz),1.08 (t, 3H, J=6.9 Hz). 13C-NMR (300 MHz, CDCl3): δ=170.30, 168.74,159.62, 152.37, 149.68, 147.22, 147.06, 132.21, 130.60, 128.99, 127.48,124.37, 119.81, 1 1 1.42, 107.97, 105.73, 102.76, 101.09, 61.95, 60.81,56.08, 55.79, 13.87, 13.82.

Synthesis of9-(3′,4′-Methylenedioxyphenyl)-4-hydroxy-6,7-dimethoxynaphtho[2,3-c]furan-l(3H)-one(20)

Two necked RBF (25 mL) was charged with LAH (0.032 g, 0.852 mmol) andanhydrous THF (4 mL) and the mixture was cooled to 0° C. with stirring.To this suspension, a solution of 19 (0.200 g, 0.426 mmol) in THF (4 mL)was added dropwise at 0° C. and stirring was continued for 2 h at sametemperature. After completion of reaction as judged by TLC (1:9,MeOH:DCM), reaction mixture was quenched with saturated sodium sulfatesolution and extracted with t-butanol (4×20 mL). Organic layer was driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The crude residue was purified by flash column chromatographyover silica gel to give yellow solid 20.

¹H-NMR (300 MHz, DMSOd6) δ=10.39 (s, 1H), 7.61 (s, I H), 7.00 (d, 1H,J=8.1 Hz), 6.94 (s, 1H), 6.85 (d, 1H, J=1.5 Hz), 6.75 (dd, 1H J=1.5, 8.4Hz), 6.10 (s, 2H), 5.35 (s, 2H), 3.93 (s, 3H), 3.64 (s, 3H). 13C-NMR(300 MHz, DMSOd6): δ=169.81, 150.66, 149.89, 147.01, 146.76, 145.05,129.71, 129.65, 128.95, 123.94, 123.45, 121.85, 1 18.86, 11 1.22,108.02, 105.63, 101.19, 100.92, 66.71, 55.78, 55.29.

LC-MS (ESI) m/z: 381 [M+H]+

Step II: Synthesis of Diphyllin Esters

General Procedure for Ester Derivatives:

To a 50 mL RBF, 20 (1 eq.), corresponding carboxylic acid (1 eq.), DMAP(10 eq.) in 20 mL of DCM was cooled (at 0° C.). The reaction mixture wasstirred for 30 min. and then DCC (1.1 eq. dissolved in cold DCM) wasadded dropwise.

The reaction was stirred at RT overnight. The reaction as monitoredusing TLC (2:98, MeOH:DCM). After completion, the solid obtained wasfiltered off and the filtrate was diluted with DCM and washed with watertwice. The combined organic layer was dried over Na₂SO₄ and concentratedunder reduced pressure. The obtained solid s purified by columnchromatography (DCM:MeOH, 98:2).

Synthesis of9-(benzo[d][1,3]dioxol-5-yl)-6,7-dimethoxy-1-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl 1-methyl-1H-pyrrole-2-carboxylate (21)

Synthesis of9-(benzo[d][1,3]dioxol-5-yl)-6,7-dimethoxy-1-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl1-methyl-1H-pyrrole-2-carboxylate (21)

To a 50 mL RBF, Diphyllin (200 mg, 5.26 mmol),1-methyl-1H-pyrrole-2-carboxylic acid (65.78 mg, 5.26 mmol), DMAP (642mg, 52.6 mmol) in 1.0 mL of DCM was cooled (at 0° C.). The reactionmixture was stirred for 30 min. and then DCC (119 mg, 5.78 mmoldissolved in cold DCM) was added dropwise. The reaction was stirred atRT overnight. The reaction was monitored using TLC (98:2, DCM:MeOH).After completion, the solid obtained was filtered off and the filtratewas diluted with DCM and washed with water twice. The combined organiclayer was dried over Na2SO4 and concentrated under reduced pressure. Theobtained solid was purified by column chromatography (DCM:MeOH, 98:2).

% Purity: 99%; LC-MS (ESI) m/z: 488 [M+H]⁺

¹H-NMR (400 MHz, CDCl3): δ=7.41-7.39 (m, 1H), 7.32 (s, 1H), 7.26 (s,1H), 7.13 (s, 1H), 6.99 (m, 2H), 6.86 (m, 2H), 6.30 (m, 1H), 6.10 (d,2H, J=17.6 Hz), 5.32 (s, 2H), 4.01 (s, 3H), 3.98 (s, 3H), 3.81 (s, 3H).

Synthesis of9-(benzo[d][1,3]dioxol-5-yl)-6,7-dimethoxy-1-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl2-cyclopentyl-2-phenylacetate (22)

Synthesis of9-(benzo[d][1,3]dioxol-5-yl)-6,7-dimethoxy-1-oxo-1,3-dihydronaphtho[2,3-c]furan-4-yl2-cyclopentyl-2-phenylacetate (22)

To a 50 mL RBF, Diphyllin (200 mg, 5.26 mmol),2-cyclopentyl-2-phenylacetic acid (107 mg, 5.26 mmol), DMAP (642 mg,52.6 mmol) in 10 mL of DCM was cooled (at 0° C.). The reaction mixturewas stirred for 30 min. and then DCC (119 mg, 5.78 mmol dissolved incold DCM) was added dropwise. The reaction was stirred at RT overnight.The reaction was monitored using TLC (98:2, DCM:MeOH). After completion,the solid obtained was filtered off and the filtrate was diluted withDCM and washed with water twice. The combined organic layer was driedover Na2SO4 and concentrated under reduced pressure. The obtained solidwas purified by column chromatography (DCM:MeOH, 98:2).

% Purity: 99%; LC-MS (ESI) m/z: 567 [M+H]⁺

¹H-NMR (400 MHz, CDCl3): δ=7.55-7.53 (m, 2H), 7.42 (m, 2H), 7.35 (m,2H), 7.05 (s, 1H), 6.96 (m, 1H), 6.80 (m, 2H), 6.66 (s, 1H), 6.06 (d,1H, J=1.6 Hz), 6.04 (d, 1H, J=1.2 Hz), 5.07 (s, 2H), 3.76 (s, 3H), 3.52(s, 3H), 2.89-2.79 (m, 1H), 2.20-2.14 (m, 1H), 1.78 (m, 1H), 1.71 (m,4H), 1.65 (m, 4H).

Example 5

Synthesis of Compound of Formula IX (Numbered as 23 in Scheme 8)

Experimental:

Synthesis of 1-(benzo[d][1,3]dioxol-5-yl)naphthalen-4-yl2-cyclopentyl-2-phenylacetate(23)

To a 50 mL RBF, 5 (200 mg, 7.5 mmol), 1-methyl-1H-pyrrole-2-carboxylicacid (93.6 mg, 7.5 mmol), DMAP (924 mg, 75 mmol) in 10 mL of DCM wascooled (at 0° C.). The reaction mixture was stirred for 30 min. and thenDCC (171.6 mg, 8.33 mmol, dissolved in cold DCM) was added dropwise. Thereaction was stirred at RT overnight. The reaction was monitored usingTLC (98:2, DCM:MeOH). After completion, the solid obtained was filteredoff and the filtrate was diluted with DCM and washed with water twice.The combined organic layer was dried over Na₂SO₄ and concentrated underreduced pressure.

The obtained solid was purified by column chromatography (DCM:MeOH,98:2).

% Purity: 99%; LC-MS (ESI) m/z: 451 [M+H]⁺

¹H NMR (400 MHz, CDCl3) δ: 7.91-7.83 (m, 1H), 7.53 (d, J=7.0 Hz, 3H),7.48 (d, J=7.4 Hz, 1H), 7.46-7.38 (m, 6H), 7.33 (d, J=7.7 Hz, 1H), 7.15(d, J=7.7 Hz, 1H), 6.91 (dd, J=2.3, 6.7 Hz, 3H), 6.04 (s, 2H), 3.74 (d,J=11.2 Hz, 1H), 2.81 (d, J=9.4 Hz, 1H), 1.92 (d, J=9.9 Hz, 1H),1.81-1.65 (m, 1H), 1.63-1.47 (m, 1H), 1.29 (d, J=25.2 Hz, 3H).

Example 6

Synthesis of Compound of Formula X (Numbered as 24 in Scheme 9)

Synthesis 1-(benzo[d][1,3]dioxol-5-yl)naphthalen-4-yl1-methyl-1H-pyrrole-2-carboxylate (24)

Experimental:

Synthesis 1-(benzo[d][1,3]dioxol-5-yl)naphthalen-4-yl1-methyl-1H-pyrrole-2-carboxylate (24)

To a 50 mL RBF, 5 (200 mg, 7.5 mmol), 2-cyclopentyl-2-phenylacetic acid(154.5 mg, 7.5 mmol), DMAP (924 mg, 75 mmol) in 10 mL of DCM was cooled(at 0° C.). The reaction mixture was stirred for 30 min. and then DCC(171.6 mg, 8.33 mmol, dissolved in cold DCM) was added dropwise. Thereaction was stirred at RT overnight. The reaction was monitored usingTLC (98:2, DCM:MeOH). After completion, the solid obtained was filteredoff and the filtrate was diluted with DCM and washed with water twice.The combined organic layer was dried over Na₂SO₄ and concentrated underreduced pressure. The obtained solid was purified by columnchromatography (DCM:MeOH, 98:2).

¹H NMR (400 MHz, CDCl₃) δ: 8.08-8.00 (m, 1H), 7.98-7.90 (in, 1H),7.55-7.42 (m, 2H), 7.46-7.37 (m, 2H), 7.35 (d, J=7.7 Hz, 1H), 7.01-6.90(m, 4H), 6.29 (dd, J=2.5, 4.0 Hz, 1H), 6.05 (s, 2H), 4.00 (s, 3H).

% Purity: 99%; LC-MS (ESI) m/z: 372 [M+H]⁺

Example 7

Synthesis of Compound of Formula XI (Numbered as 31 in Scheme 11)

Synthesis of(3S,4R,5R)-2-(1-(benzo[d][1,3]dioxol-5-yl)naphthalen-4-yloxy)-tetrahydro-2H-pyran-3,4,5-triol(31)

Experimental:

Synthesis of Tetra-O-acetyl-L-Arabinose (28)

To a 500-mL three-neck RBF equipped with guard-tube and stopper, wereadded 27 (40.0 g, 0.266 mol), pyridine (200 mL) and cooled it at 0° C.Acetic anhydride (200 mL) was added dropwise to the above mixture at 0°C. The resulting reaction mixture was stirred at 0° C. for 5 h. Afterconsumption of starting materials, as judged by TLC (5:5, EtOAc:Hexane),reaction mixture was poured into ice water (500 mL) and ether was added(200 mL). Organic layer was separated and aqueous layer was extractedwith ether (2×250 mL). Organic layers were combined and washed withsaturated cupric salt solution till free from pyridine. The organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedto give sticky solid compound 28.

¹H-NMR (300 MHz, CDCl3): δ=6.27 (d, III, J=3.6 Hz), 5.70 (t, 1H, J=9Hz), 5.06 (m, 2H), 3.97 (dd, 1H, J=6.0, 1 1.1 Hz), 3.72 (t, 1H, J=1 1.0Hz), 2.18 (s, 3H), 2.07 (s, 6H), 2.03 (s, 3H).

Synthesis of 2 Bromo 3,4,5-Tri-O-acetyl-a-L-Arabinose (29)

1 L-RBF with guard tube was charged 28 (20.0 g, 62.9 mmol) anddichloromethane (500 mL) and mixture was cooled to 0° C. in ice bath. Tothe above cold solution was added hydrogen bromide (33% in acetic acid;46 mL) with constant stirring during 1 h and reaction mixture wasfurther stirred at room temperature for 1 h. After completion ofreaction as judged by TLC (4:6, EtOAc:Hexane), reaction mixture waswashed with ice water (1×500 mL), 1% NaHCO₃ solution (1×500 mL), 10%NaHCO₃ solution (2×500 mL) and finally by brine solution (1×500 mL).Organic layer was dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to obtained white solid of 29.

¹H-NMR (300 MHz, CDCl₃): δ=6.59 (d, 1H, J=3.9 Hz), 5.60 (t, 1H, J=9.9Hz), 5.05-5.03 (m, 1H), 4.77 (dd, 1H, J=3.9, 9.6 Hz), 4.07 (dd, 1H,J=6.3, 11.4 Hz), 3.88 (t, 1H, J=11.1 Hz), 2.10 (s, 3H), 2.06 (s, 6H).

Synthesis of(3S,4R,5R)-2-(1-(benzo[d][1,3]dioxol-5-yl)naphthalen-4-yloxy)-tetrahydro-2H-pyran-3,4,5-triacetate(30)

To a 50 mL RBF, 5 (0.4 g, 1.5 mmol), 29 (0.826 g, 3.0 mmol) andtetrabutyl ammonium bromide (0.9 g, 1.5 mmol) were taken indichloromethane (20 mL) with stirring. To this suspension was added 2MNaOH (3 mL) solution and stirring was continued for 2 h at roomtemperature. After the completion of reaction as judged by TLC (4:6,EtOAc:Hexane), the reaction mixture was extracted with dichloromethane(4×20 mL). The combined organic layer washed with 10% NaOH solution(3×15 mL) followed by water (2×10 mL) and dried over anhydrous sodiumsulfate. Inorganic salts were filtered off; filtrate was concentratedunder reduced pressure and crude mass which was purified by columnchromatography using EtOAc:Hexane (40:60) as eluent to 30 as whitesolid.

Synthesis of(3S,4R,5R)-2-(1-(benzo[d][1,3]dioxol-5-yl)naphthalen-4-yloxy)-tetrahydro-2H-pyran-3,4,5-triol(31)

To a solution of 30 (0.416 g, 0.797 mmol) in methanol (20 mL) was addedsolid anhydrous K₂CO₃ (0.440 g 3.188 mmol) and reaction mixture wasstirred at room temperature for 30 min. After completion of reaction asjudged by TLC (5:95, MeOH:EtOAc), methanol was removed under reducedpressure, water was added and extracted with CH₂Cl₂ (2×25 mL). Organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedto get 31 as white fluffy solid.

¹H-NMR (400 MHz, CDCl3): δ=8.43 (m, 1H), 7.81 (m, 1H), 7.54-7.48 (m,2H), 7.31 (d, 1H, J=7.6 Hz), 7.14 (d. 1H, J=8.0 Hz), 6.94 (m, 3H), 6.03(s, 2H), 5.37 (d, 1H, J=5.2 Hz), 5.10 (d, 1H, J=6 Hz), 4.89 (d, 1H,J=5.2 Hz), 4.68 (d, 1H, J=4.4 Hz). 3.86 (m, 3H), 3.61 (m, 2H).

Example 8 Synthesis of Compound of Formula XII (Numbered as 40 in Scheme13) Synthesis ofN-(1-(benzo[d][1,3]dioxol-5-yl)naphthalen-4-yl)furan-2-carboxamide

Synthesis of 4-bromonaphthalen-1-amine (38)

Single neck RBF (500 mL) equipped with magnetic stirrer and guard tubewas charged with naphthylamine (37, 10 g, 0.069 mol) and DCM (300 mL).To this solution was added N-Bromosuccinimide (12.43 gm, 0.0698 mol)portionwise with constant stirring over half an hour at 0° C. andstirring was further continued for 1 h at room temperature. During thistime all the starting materials was consumed as confirmed by TLC (3:7,EtOAc:Hexane). Reaction mixture was added in cold water (150 mL). Thereaction mixture was extracted with dichloromethane (3×200 mL). Organiclayer was dried over anhydrous sodium sulphate and concentrated underreduced pressure. The crude mass was purified by column chromatographyover silica gel using ethyl acetate (5-20%) in hexane as eluent toafford 38 as a white solid (Yield=3.5 gm).

Synthesis of 4-(benzo[d][1,3]dioxol-5-yl)naphthalen-1-amine (39)

Single necked RBF (250 mL) equipped with magnetic stirrer, condenser andguard tube was charged with 4-bromonaphthalen-1-amine (38, 0.5 g, 2.90mmol) and 3, 4 (methylenedioxy) phenylboronic acid (0.578 gm, 3.48 mmol)in DME (7 mL). To this solution was added sodium carbonate (0.615 gm,5.80 mmol) dissolved in water (2.5 mL). Reaction mixture was stirred atrt for 10 minutes and then added tetrakis palladium (0) (0.168 gm, 0.145mmol). Reaction mixture was refluxed for 12 hrs. During this time allthe starting materials was consumed as confirmed by TLC (2:8,EtOAc:Hexane). Reaction mixture was added in water (100 mL). Thereaction mixture was extracted with ethyl acetate (3×100 mL). Organiclayer was dried over anhydrous sodium sulphate and concentrated underreduced pressure. The crude mass was purified by column chromatographyover silica gel using ethyl acetate (5-20%) in hexane as eluent toafford 39 as a white solid (Yield=0.5 gm).

Synthesis ofN-(1-(benzo[d][1,3]dioxol-5-yl)naphthalen-4-yl)furan-2-carboxamide (40)

Single neck RBF (500 mL) equipped with magnetic stirrer and guard tubewas charged with 4-(benzo[d][1,3]dioxol-5-yl)naphthalen-1-amine (39, 0.2g, 0.76 mmol), trimethylamine (0.22 mL, 1.52 mmol) and DCM (10 mL). Tothis solution was added furan-2-carbonyl chloride (0.11 mL, 1.14 mmol)dropwise with constant stirring over half an hour at 0° C. and stirringwas further continued for 12 h at room temperature. During this time allthe starting materials was consumed as confirmed by TLC (3:7,EtOAc:Hexane). Reaction mixture was added in cold water (100 mL). Thereaction mixture was extracted with dichloromethane (2×100 mL). Organiclayer was dried over anhydrous sodium sulphate and concentrated underreduced pressure. The crude mass was purified by column chromatographyover silica gel using ethyl acetate (10-30%) in hexane as eluent toafford 40 as a white solid (Yield=0.1 gm).

¹H-NMR (400 MHz, DMSO): δ=8.54 (s, 1H), 8.13 (d, 1H, J=7.6 Hz), 7.98 (t,2H, J=8.8 Hz), 7.61 (m, 2H), 7.50 (m, 2H), 7.26 (s, 1H), 6.96 (m, 3H),6.63 (m, 1H), 6.05 (s, 2H).

Example 9 Synthesis of Compound of Formula XIII (Numbered as 36 inScheme 12) Synthesis of5-(benzo[d][1,3]dioxol-5-yl)-8-(benzyloxy)quinoline hydrochloride

Experimental:

Synthesis of 8-(benzyloxy)quinoline (33)

Three necked RBF (500 mL) equipped with dropping funnel, magneticstirrer, and guard tube was charged with 8-Hydroxyquinolin (32, 5 g,0.0344 mol), potassium carbonate (9.5 gm, 0.0688 mol) and DMF (100 mL).To this solution was added benzylbromide (6.13 mL, 0.0516 mol) dropwisewith constant stirring over half an hour and stirring was furthercontinued for 12 h at room temperature. During this time all thestarting materials was consumed as confirmed by TLC (3:9, EtOAc:Hexane).Reaction mixture was added in cold water (250 mL). The reaction mixturewas extracted with ethyl acetate (3×100 mL). All the organic layercombine and washed with water (3×100 mL). Organic layer was dried overanhydrous sodium sulphate and concentrated under reduced pressure. Thecrude mass was purified by column chromatography over silica gel usingethyl acetate (5-10%) in hexane as eluent to afford 33 as a white solid(Yield=5.2 gm).

Synthesis of 8-(benzyloxy)-5-bromoquinoline (34)

Single necked RBF (250 mL) equipped with magnetic stirrer, and guardtube was charged with 8-benzyloxyquinolin (33, 4 g, 0.016 mol) in DCM(100 mL). To this solution was added N-Bromosuccinimide (3.02 gm, 0.016mol) portiowise with constant stirring over half an hour at 10° C. andstirring was further continued for 1 h at room temperature. During thistime all the starting materials was consumed as confirmed by TLC (2:8,EtOAc:Hexane). Reaction mixture was added in cold water (150 mL). Thereaction mixture was extracted with dichloromethane (3×100 mL). Organiclayer was dried over anhydrous sodium sulphate and concentrated underreduced pressure. The crude mass was purified by column chromatographyover silica gel using ethyl acetate (5-10%) in hexane as eluent toafford 34 as a white solid (Yield=3.9 gm).

Synthesis of 5-(benzo[d][1,3]dioxol-5-yl)-8-(benzyloxy)quinoline (35)

Single necked RBF (250 mL) equipped with magnetic stirrer, condenser andguard tube was charged with 8-(benzyloxy)-5-bromoquinoline (34, 1 g,0.00318 mol) and 3, 4 (methylenedioxy) phenylboronic acid (0.79 gm,0.00477 mol) in DME (20 mL). To this solution was added sodium carbonate(0.673 gm, 0.00636 mol) dissolved in water (3.2 mL). Reaction mixturewas stirred at rt for 10 minutes and then added tetrakis palladium (0)(0.183 gm, 0.000159 mol). Reaction mixture was refluxed for 12 hrs.During this time all the starting materials was consumed as confirmed byTLC (3:7, EtOAc:Hexane). Reaction mixture was added in water (100 mL).The reaction mixture was extracted with ethyl acetate (3×100 mL).Organic layer was dried over anhydrous sodium sulphate and concentratedunder reduced pressure. The crude mass was purified by columnchromatography over silica gel using ethyl acetate (10-20%) in hexane aseluent to afford 35 as a white solid (Yield=0.94 gm).

Synthesis of 5-(benzo[d][1,3]dioxol-5-yl)-8-(benzyloxy)quinolinehydrochloride (36)

Single necked RBF (250 mL) equipped with magnetic stirrer and guard tubewas charged with 5-(benzo[d][1,3]dioxol-5-yl)-8-(benzyloxy)quino line(35, 0.2 g) in dry DCM (10 mL). To this solution was added methanolicHCl at 0° C. Reaction mixture was stirred for 2 hrs at 0° C. Reactionmixture was monitored with TLC. The reaction mixture was concentratedunder reduced pressure. The crude compound was crystalized using ethylacetate and pet ether to afford 36 as a white solid (Yield=0.1 gm).

¹H-NMR (400 MHz, DMSO): δ=9.1 1 (d, 1H, J=4.4 Hz), 8.74 (d, 1H, J=8.4Hz), 7.93 (m, 1H), 7.63 (m, 4H), 7.41 (m, 3H), 7.14 (m, 2H), 7.06 (m,1H), 6.12 (s, 2H). 5.51 (s, 2H).

Example 10 Synthesis of Compound of Formula XIV (Numbered as 41 inScheme 14) Synthesis of 4-phenylnaphthalen-N,N-Di-methylsulphonamide

Experimental Synthesis of 4-phenylnaphthalen-N,N-Di-methylsulphonamide.(Comp. 41)

Single neck RBF (100 mL) equipped with magnetic stirrer and guard tubewas charged with 4-phenylnaphthalen-1-amine (39, 0.1 g, 0.45 mmol),trimethylamine (0.5 mL, 0.90 mmol) and DCM (10 mL). To this solution wasadded methane sulphonyl chloride (0.5 mL, 0.67 mmol) dropwise withconstant stirring over half an hour at 0° C. and stirring was furthercontinued for 2 h at room temperature. During this time all the startingmaterials was consumed as confirmed by TLC (1:9, EtOAc:Hexane). Reactionmixture was added in cold water (100 mL). The reaction mixture wasextracted with dichloromethane (2×100 mL). Organic layer was dried overanhydrous sodium sulphate and concentrated under reduced pressure. Thecrude mass was purified by column chromatography over silica gel usingethyl acetate (5-20%) in hexane as eluent to afford 41 as a white solid(Yield=0.15 gm).

¹H-NMR (400 MHz, DMSO): δ−8.15 (d, 1H, J−8.4 Hz), 7.94 (d, 1H, J−8.4Hz), 7.68 (m, 1H), 7.60 (m, 1H), 7.51 (m, 7H), 3.56 (s, 6H).

Example 11

Cancer Cell Assays

In Vitro Antiproliferative Assay (MTT Assay)

MTT assay is a simple and sensitive assay where, metabolic reducingactivity of the cells is measured. The increase of this activity in timeis taken as a parameter of cell growth. If treatment with a drug impairsthis increase, the action may be a consequence of growth inhibition,cell killing or both. The compounds of Formula V to XIV of the presentinvention, standard cytotoxic drug (e.g. Cisplatin) were tested atdifferent concentrations (1, 0.1, 0.01, 0.001 mM) using breast andprostate cancer cell lines. All cell lines were cultured in a 37° C.incubator with a 5% CO₂ environment. Compounds were dissolved in DMSOwith a concentration of 0.1M (stock solution). Cells were seeded into96-well plates at suitable plating efficiency.

Following Plating Efficiencies were Standardized for MTT Assay:

TABLE 1 Plating efficiency (No. of Cell lines Name of the cell linecells/well or per 200 μl) Breast MCF7 7500 MDAMB231 10000 Prostate PC310000 DU145 5000

The MTT procedure followed was as follows. Briefly, the cells wereplated in 96 well plate as per predetermined plating efficiency(Table 1) The plates were then incubated for 24 hrs in 5% CO₂ atmosphereat 37° C. Appropriate concentrations of the drugs were then added to theplate and further incubation was carried out for 48 hrs (in 5% CO₂atmosphere at 37° C.). The assay plate was then centrifuged twice at3000 rpm for 3 mins and supernatant was then discarded. 100 ul of MTTsolution (0.5 mg/ml) was then added to each well of the plate and it wasfurther incubated for 4 hrs (in 5% CO₂ atmosphere at 37° C.) Following 4hr incubation, the plate was then centrifuged twice, and supernatant wasaspirated off very carefully. 200 ul of DMSO was then added to each wellto solubilize. MTT crystals and mixed well by shaking the plate. XYgraph of log Percent viability was then plotted against log drugconcentration. 1050 (Drug concentration inhibiting the 50% of cellpopulation) was then calculated by regression analysis.

Soft Agar Assay

The Soft Agar Colony-formation Assay is an anchorage-independent growthassay in soft agar, which is one of the most stringent assays fordetecting malignant transformation of cells. For this assay, malignantcells are cultured with appropriate controls in soft agar medium for 1-2weeks. Following this incubation period, formed colonies can either beanalyzed morphologically using cell stain and quantifying the number ofcolonies formed. The results of the assay are comparable to thoseobtained after injecting tumorigenic cells into nude mice and isregarded as the “gold standard” for testing the tumorigenicity of cellsin vitro (one of the important features of cancer stem cells, CSCs).

Briefly, for Soft Agar Assay a mixture of 50 ul of 2× medium (takenappropriately as per cell line) and 50 ul of 1.2% Bacto Agar were platedon to each well of 96 well micro titer assay plate. 10 ul of cells (Ofspecific plating efficiency pre-standardized for respective cell line)were mixed with 20 ul of 2× medium and 30 ul of 0.8% of Bacto Agar and1.6 ul of drug (of appropriate concentration) in a vial and transferredto the solidified pre-layers of the assay plates. The cells were thenallowed to grow and form colonies at 37° C. and 5% CO2 for 1 week. Anintermittent feeding with 50 ul of appropriate 2× medium was performedafter 3 days of experimental set up. 16 ul of Alamar Blue (1.5 mg/ml)was then added to all the wells to quantify the developed colonies. Theplates were incubated for 24 hrs at 37° C. Absorbance was then measuredat 630 nm. XY graph of log Percent viability was then plotted againstlog drug concentration. IC50 (Drug concentration inhibiting the 50% ofcell population) was then calculated by regression analysis.

Following Plating Efficiencies Were Standardized for Soft Agar Assay:

TABLE 2 Plating efficiency (No. Cell lines Name of the cell line ofcells/well) Breast MDAMB231 7500 Prostate PC3 5000

Stem Cell Assays:

In Vitro Sphere-Forming Assay:

Sphere assay measures the ability of Cancer Stein Cells to form spheresin specially designed serum-free medium. We have used this assay tomeasure the killing efficiency of the test compounds as compared to thestandard chemotherapeutic drug, Cisplatin.

Materials and Reagents:50× B27 Supplement (Life Technologies,Invitrogen, Catalog No.: 17502-044), Fibroblast Growth Factor (FGF)(Sigma-Aldrich, Catlog No.: F029125), Epidermal Growth Factor (EGF)(Sigma-Aldrich, Catlog No.: E9644), Insulin (Sigma, Catlog No.: 19278),Dulbecco's Modified Eagle Medium/F12 (HiMedia Catlog No.: AL139-6),Dulbecco's Phosphate Buffered Saline (HiMedia Catlog No.: TL1006),Trypan Blue (TC193), Prostate Epithelial Media (LONZA, Catlog No.:CC-3166) MEGM (LONZA, Catlog No.: CC-3051), Heparin (Sigma, Catlog No.:H3393), Penstrep (HiMedia, Catlog No.: A002)

Mammosphere Media Preparation (For 100 mL): 1 g methyl celluloseautoclaved with magnetic stirrer Plain media (MEBM), 100 mL added anddissolved under magnetic stirring. After complete dissolution, add:FGF-80 μL, EGF-40 μL, Penstrep-1 mL, Heparin-400 μL.

Prostosphere Media Preparation (For 100 mL):1 g methyl celluloseautoclaved with magnetic stirrer, Plain media (Prostate Epithelial BasalMedium), 100 mL added and dissolved, under magnetic stirring. Aftercomplete dissolution, add: Insulin-40 μL, B27-2 mL, EGF-80 μL,Penstrep-1 ml.

Procedure: —The cells were trypsinised and made into single-cellsuspension by passing through cell strainers (100 μl and 40 μl,respectively), The cells were diluted at the concentration of 2000cells/100 μL and suspended in either Mammosphere (for breast cell lines)or Prostosphere (for prostate cell lines). 100 μL of this suspension wasadded into each well of 96-well suspension plates and incubated at 37°C., 5% CO₂ for 24 hrs. Appropriate concentrations of the drugs (2 μL)were added into respective wells with 100 μL of stem cell culturemedium. Plates were incubated at 37° C., 5% CO₂ for 72 hrs. Afterincubation 2.5 μL of the respective drug concentration and 50 μL of stemcell culture medium were added into each well and the plates werefurther incubated at 37° C., 5% CO₂ for 72 hrs. 3 μL of the respectivedrug concentration was added with 50 μL of stem cell culture mediumagain after incubation and plates were incubated again for 72 hrs at 37°C., 5% CO₂. Number of primary spheres formed for each concentration wascounted. A comparative graph of number of spheres formed was plottedagainst the concentration and the growth curve was compared with thepositive control.

Normal Cell Assays:

It is very important that the sensitivity of a cytotoxic drug towardsmalignant and normal cells is different. In the first place, theclinical use of drugs with a preferential toxicity towards malignantcells is preferred.

In order to test the activity of cytotoxic drugs towards normal cells,we performed MTT

Assay for these cytotoxic drugs using lymphocytes obtained from ahealthy donor.

Human lymphocytes can be readily isolated from peripheral blood.centrifuged at low speeds for 30 mins. Briefly, diluted defibrinatedfresh blood was overlaid gradually on HiSeP LSM1077 and centrifuged atlow speed for 30 mins. The lymphocyte layer (the buffy coat) (Fig) wascarefully removed in a new collection tube. The buffy coat was givenanother wash, by the diluent buffer, to reduce the plateletcontamination. The supernatant was discarded, and the pellet wasresuspended in diluent buffer. The viability was checked byHaemocytometer. Cells with Viability and Purity of 95% and more wereconsidered for the assay. MTT assay was performed with these cells asdescribed above with plating efficiency of 0.7 million/ml.

Example 12

Results of Activity of Formula V

TABLE 3 MTT Results of Formula V for Breast Cell lines IC50 inmicromolar Sr. No Cell line Cisplatin Formula V 1. MDAMB231 32.68 4.61

Table 3 indicates that activity of Formula V on breast cancer cell lineis higher compared to standard chemotherapeutic drug Cisplatin in MTTassay.

TABLE 4 MTT Results of FORMULA V for Prostate Cell lines IC50 inmicromolar Sr. No Cell line Cisplatin Formula V 1 PC3 27.99 6.19

The results indicate that activity of Formula V on prostate cancer cellline is higher compared to standard chemotherapeutic drug Cisplatin inMTT assay.

TABLE 5 Soft Agar Assay Results of Formula V for Breast Cell lines IC50in micromolar Sr. No Cell line Cisplatin Formula V 1. MDAMB231 41.7 3.45

Table 5 indicates the anticancer activity exhibited by Formula V is onbreast cancer cell line MDAMB231 is higher than standardchemotherapeutic drug Cisplatin in soft Agar Assay.

TABLE 6 Soft Agar Assay Results of Formula V for Prostate Cell linesIC50 in micromolar Sr. No Cell line Cisplatin Formula V 1 PC3 20.56 10.6

Table 6 indicates the anticancer activity of Formula V is higher onprostate cancer cell line in soft Agar Assay

TABLE 7 3D sphere count of MDAMB231 in Mammosphere media at platingefficiency of 2000 cells/well (n = 6 ± S.D) Drug Conc in uM GCD(GrowthGC(Growth Control With 250 25 2.5 0.25 0.025 Control) DMSO) Cisplatin18(±2) 31(±3) 35(±2) 42(±3) 50(±3) 85(±3) 76(±4) FORMULA V  0(±0)  7(±2)12(±1) 24(±3) 40(±3) 85(±3) 76(±4)

Table 7 indicates Formula V is effective on spheres of MDAMB231 comparedto standard chemotherapeutic drug Cisplatin.

TABLE 8 3D sphere count of PC3 in Prostosphere media at platingefficiency of 2000 cells/well (n = 6 ± S.D) Drug Conc in uM GCD(GrowthGC(Growth Control With 250 25 2.5 0.25 0.025 Control) DMSO) Cisplatin25(±3) 32(±2) 40(±3) 47(±5) 58(±4) 77(±5) 65(±4) FORMULA V  0(±0) 21(±4)36(±3) 40(±5) 50(±5) 77(±5) 65(±4)

Table 8 indicates that Formula V is more effective on spheres of PC3compared to standard chemotherapeutic drug Cisplatin.

Example 13

Results of Activity of Formula VI

TABLE 9 MTT Results of Formula VI for Breast Cell lines IC50 inmicromolar Sr. No Cell line Cisplatin Formula VI 1. MDAMB231 32.68 10.09

Table 9 indicates that activity of Formula VI on breast cancer cell lineis higher compared to standard chemotherapeutic drug Cisplatin in MTTassay.

TABLE 10 MTT Results of Formula VI for Prostate Cell lines IC50 inmicromolar Sr. No Cell line Cisplatin Formula VI 1 PC3 27.99 5.65

Table 10. indicates that activity of FORMULA VI on Prostrate cancer cellline is higher compared to standard chemotherapeutic drug Cisplatin inMTT assay.

Results of MTT assay indicates that compound of Formula VI exhibitshigher anticancer activity on breast and prostate Cancer cell linescompared to standard chemo therapeutic drug Cisplatin.

TABLE 11 Soft Agar Assay Results of Formula VI for Breast Cell linesIC50 in micromolar Sr. No Cell line Cisplatin Formula VI 1. MDAMB23124.79 14.22

Table 11 indicates the anticancer activity of Formula VI is higher onbreast cancer cell line MDAMB231 compared to standard chemotherapeuticdrug Cisplatin in soft Agar Assay.

TABLE 12 Soft Agar Assay Results of Formula VI for Prostate Cell linesIC50 in micromolar Sr. No Cell line Cisplatin Formula VI 1 PC3 21.303.25

Table 12 indicates the anticancer activity of Formula. VI is higher onprostate cancer cell line PC3 compared to standard chemotherapeutic drugCisplatin in soft Agar Assay

The results Indicates that Formula VI exhibits higher anticanceractivity on breast and prostate Cancer cell lines compared to standardchemotherapeutic drug Cisplatin in Soft Agar Assay.

TABLE 13 3D sphere count of MDAMB231 in Mammosphere media at platingefficiency of 2000 cells/well (n = 6 ± S.D) Drug Conc in uM GCD(GrowthGC(Growth Control With 250 25 2.5 0.25 0.025 Control) DMSO) Cisplatin18(±2) 31(±3) 35(±2) 42(±3) 50(±3) 85(±3) 76(±4) FORMULA VI  0(±0) 7(±2) 24(±3) 36(±2) 44(±3) 85(±3) 76(±4)

Table 13 indicates that Formula VI is more effective on spheres ofMDAMB231 compared to standard chemotherapeutic drug Cisplatin.

TABLE 14 3D sphere count of PC3 in Prostosphere media at platingefficiency of 2000 cells/well (n = 6 ± S.D) Drug Conc in uM GCD (GrowthGC(Growth Control With 250 25 2.5 0.25 0.025 Control) DMSO) Cisplatin25(±3) 32(±2) 40(±3) 47(±5) 58(±4) 77(±5) 65(±4) Formula VI  0(±0)21(±2) 30(±2) 28(±2) 40(±3) 77(±5) 65(±4)

Table 14 indicates that Formula VI is more effective on spheres of PC3compared to standard chemotherapeutic drug Cisplatin.

Example 14

Results of Activity of Formula VII

TABLE 15 MTT Results of Formula VII for Breast Cancer Cell lines IC50 inmicromolar Sr. No Cell line Cisplatin FORMULA VII 1. MCF-7 29.57 2.78 2.MDAMB231 38.46 2.04

Table 15 indicates that activity of Formula VII on breast cancer celllines is higher compared to standard chemotherapeutic drug Cisplatin inMTT assay.

TABLE 16 MTT Results Formula VII for Prostate Cancer Cell lines IC50 inmicromolar MSP008-7 Sr. No Cell line Cisplatin (FORMULA VII) 1. PC329.02 6.32 2. DU145 23.86 3.57

Table 16 indicates that activity of Formula VII on prostate cancer celllines is higher compared to standard chemotherapeutic drug Cisplatin inMTT assay.

TABLE 17 Soft Agar Assay Results of Formula VII for Breast Cell linesIC50 in micromolar Sr. No Cell line Cisplatin Formula VII 1. MDAMB23124.79 7.91

Table 17 indicates the anticancer activity of FORMULA VII is higher onbreast cancer cell line MDAMB231 compared to standard chemotherapeuticdrug Cisplatin in soft Agar Assay.

TABLE 18 Soft Agar Assay Results of Formula VII for Prostate Cell linesIC50 in micromolar Sr. No Cell line Cisplatin Formula VII 1 PC3 21.300.36

Table 18 results indicate the anticancer activity of Formula VII ishigher on prostate cancer cell line PC3 compared to standardchemotherapeutic drug Cisplatin in soft Agar Assay.

In Vitro Sphere-Forming Assay

TABLE 19 3D sphere count of MDAMB231 in Mammosphere media at platingefficiency of 2000 cells/well (n = 6 ± S.D) Drug Conc in uM GCD(GrowthGC(Growth Control With 250 25 2.5 0.25 0.025 Control) DMSO) Cisplatin23(±5) 38(±8) 51(±5) 69(±7) 89(±4) 86(±6) 78(±2) FORMULA VII  0(±0)40(±3) 40(±7) 46(±7) 47(±4) 86(±6) 78(±2)

Table 19 indicates the that Formula VII is more effective on spheres ofMDAMB231 compared to standard chemotherapeutic drug Cisplatin.

TABLE 20 3D sphere count of PC3 in Prostosphere media at platingefficiency of 2000 cells/well (n = 6 ± S.D) Drug Conc in uM GCD(GrowthGC(Growth Control With 250 25 2.5 0.25 0.025 Control) DMSO) Cisplatin30(±5) 31(±5) 41(±4) 49(±7) 47(±4) 68(±8) 62(±2) FORMULA VII  0(±0) 9(±2) 23(±3) 31(±5) 64(±8) 68(±8) 62(±2)

Table 20 indicates that Formula VII is more effective on spheres of PC3compared to standard chemotherapeutic drug Cisplatin.

Example 15

Results of Activity Formula VIII

TABLE 21 MTT Results of Formula VIII for Breast Cell lines IC50 inmicromolar Sr. No Cell line Cisplatin Formula VIII 1. MCF-7 29.57 1.052. MDAMB231 38.46 3.14

Table 21 indicates that activity of FORMULA VIII on breast cancer celllines is higher compared to standard therapeutic drug Cisplatin in MTTassay.

TABLE 22 MTT Results of Formula VIII for Prostate Cell lines IC50 inmicromolar Sr. No Cell line Cisplatin Formula VIII 1. PC3 29.02 3.91 2.DU145 23.86 4.28

Table 22 indicates that activity of Formula VIII on prostate cancer celllines is higher compared to standard therapeutic drug Cisplatin in MTTassay.

TABLE 23 Soft Agar Assay Results of Formula VIII for Breast Cell linesIC50 in micromolar Sr. No Cell line Cisplatin Formula VIII 1. MDAMB23124.79 1.32

Table 23 indicates the anticancer activity of Formula VIII is higher onbreast cancer cell line MDAMB231 compared to standard therapeutic drugCisplatin in soft Agar Assay.

TABLE 24 Soft Agar Assay Results of Formula VIII for Prostate Cell linesIC50 in micromolar Sr. No Cell line Cisplatin Formula VIII 1 PC3 21.301.96

Table 24 indicates the anticancer activity of Formula VIII is higher onprostate cancer cell line PC3 compared to standard therapeutic drugCisplatin in soft Agar Assay.

TABLE 25 3D sphere count of MDAMB231 in Mammosphere media at platingefficiency of 2000 cells/well (n = 6 ± S.D) Drug Conc in uM GCD(GrowthGC (Growth Control With 250 25 2.5 0.25 0.025 Control) DMSO) Cisplatin23(±5) 38(±8) 51(±5) 69(±7) 89(±4) 86(±6) 78(±2) Formula VIII  0(±0) 8(±2) 13(±2) 29(±4) 36(±3) 86(±6) 78(±2)

Table 25 indicates the that Formula VIII is more effective on spheres ofMDAMB231 compared to standard therapeutic drug Cisplatin

TABLE 26 3D sphere count of PC3 in Prostosphere media at platingefficiency of 2000 cells/well (n = 6 ± S.D) Drug Conc in uM GCD(GrowthGC(Growth Control With 250 25 2.5 0.25 0.025 Control) DMSO) Cisplatin30(±5) 31(±5) 41(±4) 49(±7) 47(±4) 68(±8) 62(±2) Formula VIII  0(±0) 8(±2) 13(±3) 24(±3) 29(±3) 68(±8) 62(±2)

Table 26 indicates that Formula VIII is more effective on spheres of PC3compared to standard chemotherapeutic drug Cisplatin

Example 16

Results of Activity of Formula IX

TABLE 27 MTT Results of Formula IX for Breast Cell lines IC50 inmicromolar Sr. No. Cell line Cisplatin FORMULA IX 1. MCF-7 29.57 5.24 2.MDAMB231 38.46 5.26

Table 27 indicates that activity of FORMULA IX on breast cancer celllines is higher compared to standard chemotherapeutic drug Cisplatin inMTT assay.

TABLE 28 MTT Results of Formula IX for Prostate Cell lines IC50 inmicromolar Sr. No Cell line Cisplatin Formula IX 1. PC3 29.02 5.62 2.DU145 23.86 8.91

Table 28 indicates that activity of Formula IX on prostate cancer celllines is higher compared to standard chemotherapeutic drug Cisplatin inMTT assay.

TABLE 29 Soft Agar Assay Results of Formula IX for Breast Cell linesIC50 in micromolar Sr. No Cell line Cisplatin Formula IX 1. MDAMB23124.79 2.12

Table 29 indicates the anticancer activity of Formula IX is higher onbreast cancer cell line MDAMB231 compared to standard chemotherapeuticdrug Cisplatin in soft Agar Assay.

TABLE 30 Soft Agar Assay Results of Formula IX for Prostate Cell linesIC50 in micromolar Sr. No Cell line Cisplatin Formula IX 1 PC3 21.304.81

Table 30 indicates the anticancer activity of Formula IX is higher onprostate cancer cell line PC3 compared to standard chemotherapeutic drugCisplatin in soft Agar Assay.

TABLE 31 3D sphere count of MDAMB231 in Mammosphere media at platingefficiency of 2000 cells/well (n = 6 ± S.D) Drug Conc in uM GCD(GrowthGC (Growth Control With 250 25 2.5 0.25 0.025 Control) DMSO) Cisplatin31(±4) 37(±4) 43(±2) 48(±2) 62(±6) 82(±4) 74(±3) Formula IX  0(±0)22(±3) 26(±3) 40(±5) 52(±4) 82(±4) 74(±3)

Table 31 indicates that Formula IX is more effective on spheres ofMDAMB231 compared to standard chemotherapeutic drug Cisplatin.

TABLE 32 3D sphere count of PC3 in Prostosphere media at platingefficiency of 2000 cells/well (n = 6 ± S.D) Dilution (from stock of0.1M) Final conc 10 100 1000 10,000 100,000 250 μM 25 μM 2.5 μM 0.25 μM0.025 μM GC GCD Cisplatin 22(±4) 33(±3) 46(±2) 55(±5) 62(±5) 68(±2)56(±2) Formula IX  0(±0) 31(±3) 37(±5) 44(±4) 60(±7) 68(±2) 56(±2)

Table 32 indicates that Formula IX is more effective on spheres of PC3compared to standard chemotherapeutic drug Cisplatin.

Example 17

Results of Activity of FORMULA X

TABLE 33 MTT Results of Formula X for Breast Cell lines IC50 inmicromolar Sr. No Cell line Cisplatin Formula X 1. MCF-7 32.35 3.46 2.MDAMB231 36.98 3.16

Table 33 indicates that activity of Formula X on breast cancer celllines is higher compared to standard chemotherapeutic drug Cisplatin inMTT assay.

TABLE 34 MTT Results of Formula X for Prostate Cell lines IC50 inmicromolar Sr. No. Cell line Cisplatin Formula X 1. PC3 40.73 2.6 2.DU145 42.95 3.28

Table 34 indicates that activity of Formula X on prostate cancer celllines is higher compared to standard chemotherapeutic drug Cisplatin inMTT assay.

TABLE 35 Soft Agar Assay Results of Formula X for Breast Cell lines IC50in micromolar MSP008- Sr. No Cell line Cisplatin 44(FORMULA X) 1.MDAMB231 37.33 2.07

Table 35 indicates the anticancer activity of Formula X is higher onbreast cancer cell line MDAMB231 compared to standard chemotherapeuticdrug Cisplatin in soft Agar Assay.

TABLE 36 Soft Agar Assay Results of Formula X for Prostate Cell linesIC50 in micromolar Sr. No Cell line Cisplatin Formula X 1 PC3 23.77 2.38

Table 36 indicates the anticancer activity of Formula X is higher onprostate cancer cell line PC3 compared to standard chemotherapeutic drugCisplatin in soft Agar Assay.

In Vitro Sphere-Forming Assay

TABLE 37 3D sphere count of MDAMB231 in Mammosphere media at platingefficiency of 2000 cells/well (n = 6 ± S.D) Drug Conc in uM GCD(GrowthGC(Growth Control With 250 25 2.5 0.25 0.025 Control) DMSO) Cisplatin31(±4) 37(±4) 43(±2) 48(±2) 62(±6) 82(±4) 74(±3) Formula X  0(±0) 24(±3)28(±3) 37(±4) 39(±4) 82(±4) 74(±3)

Table 37 indicates that Formula X is more effective on spheres ofMDAMB231 compared to standard chemotherapeutic drug Cisplatin.

Example 18

Results of Activity of Formula XI

TABLE 38 MTT Results of Formula XI for Breast Cell lines IC50 inmicromolar Sr. No Cell line Cisplatin Formula XI 1. MCF-7 32.35 4.36 2.MDAMB231 36.98 9.77

Table 38 indicates that activity of Formula XI on breast cancer celllines is higher compared to standard chemotherapeutic drug Cisplatin inMTT assay.

TABLE 39 MTT Results of Formula XI for Prostate Cell lines IC50 inmicromolar Sr. No Cell line Cisplatin Formula XI 1. PC3 40.73 4.16 2.DU145 42.95 10.23

Table 39 indicates that activity of FORMULA XI on prostate cancer celllines is higher compared to standard chemotherapeutic drug Cisplatin inMTT assay.

TABLE 40 Soft Agar Assay Results of Formula XI for Breast Cell linesIC50 in micromolar Sr. No Cell line Cisplatin Formula XI 1. MDAMB23137.33 2.08

Table 40 indicates the anticancer activity of Formula XI is higher onbreast cancer cell line MDAMB231 compared to standard chemotherapeuticdrug Cisplatin in soft Agar Assay.

TABLE 41 Soft Agar Assay Results of Formula XI for Prostate Cell linesIC50 in micromolar Sr. No Cell line Cisplatin Formula XI 1 PC3 23.7718.84

Table 41 indicates the anticancer activity of Formula XI is higher onprostate cancer cell line PC3 compared to standard chemotherapeutic drugCisplatin in soft Agar Assay.

Example 19

Results of Activity of Formula XII

TABLE 42 MTT Results of Formula XII for Breast Cell lines IC50 inmicromolar Sr. No Cell line Cisplatin Formula XII 1. MCF-7 32.96 4.95 2.MDAMB231 32.73 3.37

Table 42 indicates that activity of Formula XII on breast cancer celllines is higher compared to standard chemotherapeutic drug Cisplatin inMTT assay.

TABLE 43 MTT Results of Formula XII for Prostate Cell lines IC50 inmicromolar Sr. No Cell line Cisplatin Formula XII 1. PC3 35.81 19.63 2.DU145 34.43 9.82

Table 43 indicates that activity of Formula XII on prostate cancer celllines is higher compared to standard chemotherapeutic drug Cisplatin inMTT assay.

TABLE 44 Soft Agar Assay Results of Formula XII for Breast Cell linesIC50 in micromolar Sr. No Cell line Cisplatin Formula XII 1. MDAMB23123.93 2.14

Table 44 indicates the anticancer activity of Formula XII is higher onbreast cancer cell line MDAMB231 compared to standard chemotherapeuticdrug Cisplatin in soft Agar Assay.

TABLE 45 Soft Agar Assay Results of Formula XII for Prostate Cell linesIC50 in micromolar Sr. No Cell line Cisplatin Formula XII 1 PC3 21.883.36

Table 45 indicates the anticancer activity of Formula XII is higher onprostate cancer cell line PC3 compared to standard chemotherapeutic drugCisplatin in soft Agar Assay.

In Vitro Sphere-Forming Assay

TABLE 46 3D sphere count of MDAMB231 in Mammosphere media at platingefficiency of 2000 cells/well (n = 6 ± S.D) Drug Conc in uM GCD(GrowthGC (Growth Control With 250 25 2.5 0.25 0.025 Control) DMSO) Cisplatin26(±3) 35(±2) 46(±3) 58(±3) 67(±2) 72(±3) 64(±2) Formula XII  0(±0) 8(±1) 17(±2) 27(±2) 31(±2) 72(±3) 64(±2)

Table 46 indicates that Formula XII is more effective on spheres ofMDAMB231 compared to standard chemotherapeutic drug Cisplatin.

TABLE 47 3D sphere count of PC3 in Prostosphere media at platingefficiency of 2000 cells/well (n = 6 ± S.D) Drug Conc in uM GCD(GrowthGC(Growth Control With 250 25 2.5 0.25 0.025 Control) DMSO) Cisplatin21(±2) 32(±3) 39(±2) 42(±3) 45(±2) 80(±5) 76(±4) Formula XII  0(±0)15(±2) 23(±2) 28(±3) 37(±3) 80(±5) 76(±4)

Table 47 indicates that Formula XII is more effective on spheres of PC3compared to standard chemotherapeutic drug Cisplatin.

Example 20

Results of Activity of Formula XIII

TABLE 48 MTT Results Formula XIII for Breast Cell lines IC50 inmicromolar Sr. No Cell line Cisplatin Formula XIII 1. MDAMB231 35.488.00

Table 48 indicates that activity of Formula XIII on breast cancer celllines is higher compared to standard chemotherapeutic drug Cisplatin inMTT assay.

TABLE 49 MTT Results of Formula XIII for Prostate Cell lines IC50 inmicromolar Sr. No Cell line Cisplatin Formula XIII 1. PC3 36.39 4.33 2.DU145 35.48 4.06

Table 49 indicates that activity of Formula XIII on prostate cancer celllines is higher compared to standard chemotherapeutic drug Cisplatin inMTT assay.

TABLE 50 Soft Agar Assay Results of Formula XIII for Breast Cell linesIC50 in micromolar Sr. No Cell line Cisplatin Formula XIII 1. MDAMB23123.93 2.68

Table 50 indicates the anticancer activity of Formula XIII is higher onbreast cancer cell line MDAMB231 compared to standard chemotherapeuticdrug Cisplatin in soft Agar Assay.

TABLE 51 Soft Agar Assay Results of Formula XIII for Prostate Cell linesIC50 in micromolar Sr. No Cell line Cisplatin Formula XIII 1 PC3 21.886.32

Table 51 indicates the anticancer activity of Formula XIII is higher onprostate cancer cell line PC3 compared to standard chemotherapeutic drugCisplatin in soft Agar Assay.

In Vitro Sphere-Forming Assay

TABLE 52 3D sphere count of MDAMB231 in Mammosphere media at platingefficiency of 2000 cells/well (n = 6 ± S.D) Drug Conc in uM GCD(GrowthGC(Growth Control With 250 25 2.5 0.25 0.025 Control) DMSO) Cisplatin26(±3) 35(±2) 46(±3) 58(±3) 67(±2) 72(±3) 64(±2) Formula XIII  0(±0)13(±2) 27(±2) 36(±3) 45(±2) 72(±3) 64(±2)

Table 52 indicates that Formula XIII is more effective on spheres ofMDAMB231 compared to standard chemotherapeutic drug Cisplatin.

TABLE 53 3D sphere count of PC3 in Prostosphere media at platingefficiency of 2000 cells/well (n = 6 ± S.D) Drug Conc in uM GCD(GrowthGC(Growth Control With 250 25 2.5 0.25 0.025 Control) DMSO) Cisplatin21(±2) 32(±3) 39(±2) 42(±3) 45(±2) 80(±5) 76(±4) FORMULA XIII  0(±0)14(±1) 27(±3) 39(±5) 41(±7) 80(±5) 76(±4)

Table 53 indicates that Formula XIII is more effective on spheres of PC3compared to standard chemotherapeutic drug Cisplatin.

Example 21

Results of Activity of Formula XIV

TABLE 54 Soft Agar Assay Results of Formula XIV on Breast Cell linesIC50 in micromolar Sr. No Cell line Cisplatin Formula XIV 1. MDAMB23124.79 3.12

Table 54 indicates the anticancer activity of Formula XIV is higher onbreast cancer cell line MDAMB231 compared to standard chemotherapeuticdrug Cisplatin in soft Agar Assay.

TABLE 55 3D sphere count of MDAMB231 in Mammosphere media at platingefficiency of 2000 cells/well (n = 6 ± S.D) Drug Conc in uM GCD(GrowthGC (Growth Control With 250 25 2.5 0.25 0.025 Control) DMSO) Cisplatin26(±3) 35(±2) 46(±3) 58(±3) 67(±2) 72(±3) 64(±2) Formula XIV 0(±0)22(±3) 28(±3) 35(±2) 38(±5) 72(±3) 64(±2)

Table 55. indicates that Formula XIV is more effective on spheres ofMDAMB231 compared to standard chemotherapeutic drug Cisplatin.

TABLE 56 3D sphere count of PC3 in Prostosphere media at platingefficiency of 2000 cells/well (n = 6 ± S.D) Drug Conc in uM GCD(GrowthGC(Growth Control With 250 25 2.5 0.25 0.025 Control) DMSO) Cisplatin21(±2) 32(±3) 39(±2) 42(±3) 45(±2) 80(±5) 76(±4) Formula XIV  0(±0)13(±1) 20(±2) 29(±5) 36(±2) 80(±5) 76(±4)

Table 56 indicates that Formula XIV is more effective on spheres of PC3compared to standard chemotherapeutic drug Cisplatin.

What is claimed is:
 1. A compound of Formula IV:

R⁶ and R⁷ each independently is selected from —H, or alkoxy; R isselected from:

R¹³ is —OH; R¹⁴ is selected from alkoxy, or —OH; R¹⁵ is selected fromalkoxy, or —OH; R¹⁶ is —H; R¹⁷ is alkyl; R¹¹ and R¹² each independentlyis selected from —H, substituted or unsubstituted 5-membered lactonering, —C(O)O-alkyl; when R is

R¹¹ and R¹² are not together as lactone; and when R¹³ is —OH and, R¹⁴and R¹⁵ are -alkoxy; then R¹⁶ is —H; R⁶, R⁷, R¹¹ and R¹² are not —H. 2.The compound as claimed in claim 1, wherein the compound is compound ofFormula VI:


3. The compound as claimed in claim 1, wherein the compound is compoundof Formula VII:


4. The compound as claimed in claim 1, wherein the compound is compoundof Formula VIII:


5. The compound as claimed in claim 1, wherein the compound is compoundof Formula IX:


6. The compound as claimed in claim 1, wherein the compound is compoundof Formula X:


7. The compound as claimed in claim 1, wherein the compound is compoundof Formula XI:


8. The compound as claimed in claim 1 for use in the treatment ofcancer.
 9. The compound as claimed in claim 8, wherein the cancer isbreast, oral, prostate, brain, blood, bone marrow, liver, pancreas,skin, kidney, colon, ovary, lung, testicle, penis, thyroid, parathyroid,pituitary, thymus, retina, uvea, conjunctiva, spleen, head, neck,trachea, gall bladder, rectum, salivary gland, adrenal gland, throat,esophagus, lymph nodes, sweat glands, sebaceous glands, muscle, heart,and stomach cancer.
 10. The compound as claimed in claim 8, wherein thecancer is breast or prostate.
 11. A pharmaceutical compositioncomprising the compound as claimed in claim 1 and a pharmaceuticallyacceptable excipient including carrier, adjuvant, vehicle or mixturesthereof.